U.S. patent number 7,902,236 [Application Number 12/365,643] was granted by the patent office on 2011-03-08 for antagonists of the vanilloid receptor subtype 1 (vr1) and use thereof.
This patent grant is currently assigned to Abbott Laboratories. Invention is credited to Dilinie P. Fernando, Arthur Gomtsyan, Margaret Chi-Ping Hsu, John R. Koenig, Chih-Hung Lee, Richard J. Perner.
United States Patent |
7,902,236 |
Gomtsyan , et al. |
March 8, 2011 |
**Please see images for:
( Certificate of Correction ) ** |
Antagonists of the vanilloid receptor subtype 1 (VR1) and use
thereof
Abstract
The present invention is directed to compounds of formula (I)
##STR00001## wherein variables W, X, Y, D, A, n, R.sub.1, R.sub.2
and R.sub.9 are as defined in the description.
Inventors: |
Gomtsyan; Arthur (Vernon Hills,
IL), Perner; Richard J. (Gurnee, IL), Koenig; John R.
(Chicago, IL), Hsu; Margaret Chi-Ping (Lake Forest, IL),
Fernando; Dilinie P. (Lake Forest, IL), Lee; Chih-Hung
(Vernon Hills, IL) |
Assignee: |
Abbott Laboratories (Abbott
Park, IL)
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Family
ID: |
37056909 |
Appl.
No.: |
12/365,643 |
Filed: |
February 4, 2009 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20100010055 A1 |
Jan 14, 2010 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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11431459 |
May 10, 2006 |
7504520 |
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60679708 |
May 11, 2005 |
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Current U.S.
Class: |
514/365; 514/377;
514/376; 514/370; 514/374; 514/369 |
Current CPC
Class: |
A61P
13/02 (20180101); A61P 37/08 (20180101); A61P
13/10 (20180101); A61P 29/00 (20180101); A61P
7/12 (20180101); A61P 25/02 (20180101); A61P
43/00 (20180101); C07D 263/48 (20130101); A61P
25/04 (20180101); A61P 13/00 (20180101) |
Current International
Class: |
A61K
31/426 (20060101); A61K 31/421 (20060101) |
Field of
Search: |
;514/365,369,370,374,376,377 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO-0230358 |
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Apr 2002 |
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WO |
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WO-2004072068 |
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Aug 2004 |
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WO |
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WO-2004110350 |
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Dec 2004 |
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WO |
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WO-2006044527 |
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Apr 2006 |
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WO |
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Other References
Caterina et al., "Impaired Nociception and Pain Sensation in Mice
Lacking the Capsaicin Receptor," Science, 2000, 306-313, vol. 288.
cited by other .
Davis et al., "Vanilloid receptor-1 is essential for inflammatory
thermal hyperalgesia," (Binary/Image), 2000, 183-187, vol. 405.
cited by other .
Fowler, C. "Intravesical Treatment of Overactive Bladder," Urology,
2000, 60-64, vol. 55. cited by other .
International Search Report for application No. PCT/US2006/0018256,
Mailed on Oct. 26, 2006, 2 pages. cited by other .
Nolano et al., "Topical Capsaicin in Humans: Parallel Loss of
Epidermal Nerve Fibers and Pain Sensation," (Binary/Image), 1999,
135-145, vol. 81. cited by other .
Pircio, A.W. et al., "A New Method for the Evaluation of Analgesic
Activity Using Adjuvant-Induced Arthritis in the Rat," Eur Journal
of Pharmacology, 1975, 207-215, vol. 31. cited by other .
Rasmussen and Bowadt. "Ketene Chemistry 2 A General Procedure for
the Synthesis of 2-Alkoxycyclopropane-carboxylic Esters and Acids
Starting from Aldehydes and Ketene," Synthesis, 1989, 114-117.
cited by other .
Wolff "Burger's Medicinal Chemistry", 1994, 5th Ed, vol. 1,
975-977. cited by other.
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Primary Examiner: Anderson; Rebecca L
Assistant Examiner: Shterengarts; Samantha L
Attorney, Agent or Firm: Parial; Andrew M.
Parent Case Text
This application is a Division of U.S. patent application Ser. No.
11/431,459 filed on May 10, 2006; which is a provisional of U.S.
Patent Application Ser. No. 60/679,708 filed May 11, 2005, all of
which are incorporated herein by reference.
Claims
What is claimed is:
1. A method of treating a disorder selected from the group
consisting of neuropathic pain, allodynia, inflammatory pain,
inflammatory hyperalgesia, bladder overactivity, urinary
incontinence, and thermal hyperalgesia, wherein the disorder is
ameliorated by inhibiting vanilloid receptor subtype 1 (VR1) in a
host mammal in need of such treatment comprising administering a
therapeutically effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, wherein formula (I) is
##STR00010## wherein, A is O or --N(R.sub.3); D is --N(R.sub.4), O
or S; R.sub.3 and R.sub.1 are each independently selected from the
group consisting of hydrogen, alkyl, --C(O)alkyl, and
--S(O).sub.2(alkyl); R.sub.1 and R.sub.2 are each independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
cyano, nitro, halogen, --OR.sub.5, --OC(O)R.sub.5, --SR.sub.5, --S
(O).sub.2R.sub.5, --S (O).sub.2OR.sub.5, --S
(O).sub.2N(R.sub.5)(R.sub.6), --N(R.sub.5)(R.sub.6),
--N(R.sub.6)C(O)R.sub.5, --N(R)C(O)N(R.sub.5,
--N(R)S(O).sub.2N(R.sub.6), --C(O)R.sub.5, --C(O)OR.sub.5,
--C(O)N(R.sub.5)(R.sub.6), haloalkyl, -alkylenyl-OR.sub.5,
-alkylenyl-OC(O)R.sub.5, -alkylenyl-SR.sub.5,
-alkylenyl-S(O)R.sub.5 alkylenyl-S(O).sub.2OR.sub.5,
-alkylenyl-S(O).sub.2N(R.sub.5)(R.sub.6),
-alkylenyl-N(R.sub.5)(R.sub.6), -alkylenyl-N(R.sub.6), C(O)R.sub.5,
alkylenyl-N(R.sub.6)C(O)N(R.sub.5)(R.sub.6),
-alkylenyl-N(R.sub.6)S(O).sub.2N(R.sub.5)(R.sub.6),
-alkylenyl-C(O)R.sub.5, -alkylenyl-C(O)OR.sub.5,
-alkylenyl-C(O)N(R.sub.5)(R.sub.6), --R.sub.7, and
-alkylenyl-R.sub.7; provided that when one of R.sub.1 and R.sub.2
is hydrogen, the other is not hydrogen; R.sub.5 at each occurrence
is independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl and benzyl; R.sub.6 at each occurrence is
independently selected from the group consisting of hydrogen and
alkyl; R.sub.7 at each occurrence is independently selected from
the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl
and heteroaryl; wherein each R.sub.7 is independently substituted
with 0, 1, 2, 3, 4 or 5 substituents independently selected from
the group consisting of alkyl, alkenyl, halogen, cyano, nitro,
hydroxy, alkoxy, haloalkoxy, --S(alkyl), --S(O).sub.2(alkyl),
--N(H).sub.2, --N(H)(alkyl), --N(alkyl).sub.2, --N(H)C(O)alkyl,
--C(O)OH, --C(O)Oalkyl, --C(O)NH.sub.2, --C(O)N(H)alkyl,
--C(O)N(alkyl).sub.2, --R.sub.8, cyanoalkyl, haloalkyl,
hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylenyl-S(alkyl),
-alkylenyl-S(O).sub.2(alkyl), -alkylenyl-N(H).sub.2,
-alkylenyl-N(H)(alkyl), -alkylenyl-N(alkyl).sub.2,
-alkylenyl-N(H)C(O)alkyl, -alkylenyl-C(O)OH, -alkylenyl-C(O)Oalkyl,
-alkylenyl-C(O)NH.sub.2, -alkylenyl-C(O)N(H)alkyl,
-alkylenyl-C(O)N(alkyl).sub.2, and -alkylenyl-R.sub.8; R.sub.8 at
each occurrence is independently selected from the group consisting
of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl;
wherein each R.sub.8 is independently substituted with 0, 1, 2, 3,
4 or 5 substituents independently selected from the group
consisting of alkyl, alkenyl, halogen, cyano, nitro, hydroxy,
alkoxy, haloalkoxy, --S(alkyl), --S(O).sub.2(alkyl), --N(H).sub.2,
--N(H)(alkyl), --N(alkyl).sub.2, --N(H)C(O)alkyl, --C(O)OH,
--C(O)Oalkyl, --C(O)NH.sub.2, --C(O)N(H)alkyl,
--C(O)N(alkyl).sub.2, cyanoalkyl, haloalkyl, hydroxyalkyl,
alkoxyalkyl, haloalkoxyalkyl, -alkylenyl-S(alkyl),
-alkylenyl-S(O).sub.2(alkyl), -alkylenyl-N(H).sub.2,
-alkylenyl-N(H)(alkyl), -alkylenyl-N(alkyl).sub.2,
-alkylenyl-N(H)C(O)alkyl, -alkylenyl-C(O)OH, -alkylenyl-C(O)Oalkyl,
-alkylenyl-C(O)NH.sub.2, -alkylenyl-C(O)N(H)alkyl, and
-alkylenyl-C(O)N(alkyl).sub.2; W and Y are each independently
selected from the group consisting of --C(R).sub.x(R.sub.y)-- and
--N(R.sub.z)--; provided that when one of W and Y is
--N(R.sub.z)--, then the other is --C(R.sub.x)(R.sub.y)--; X is
selected from the group consisting of --C(O)--,
--C(R.sub.x)(R.sub.y)--, --N--C(R.sub.x), --C(R.sub.x),
--C(R.sub.x)(R.sub.y)--C(R.sub.x)(R.sub.y)--,
--C(O)--C(R.sub.x)(R.sub.y)--, --C(R.sub.x)(R.sub.y)--C(O)--,
--C(R.sub.x)(R.sub.y)--N(R.sub.z)-- and --N(R.sub.x)(R.sub.y)--;
provided that when one of W and Y is --N(R.sub.z)--, then X is
selected from the group consisting of --C(R.sub.x)(R.sub.y)-- and
--C(R.sub.x)(R.sub.y)--C(R.sub.x)(R.sub.y)--; R.sub.x and R.sub.y,
at each occurrence are each independently selected from the group
consisting of hydrogen, alkyl, haloalkyl, --OR.sub.a,
--OC(O)R.sub.a, SR.sub.a, --S(O)R.sub.a,
--S(O).sub.2N(R.sub.a)(R.sub.b), --S(O).sub.2OR.sub.a,
--N(R.sub.a)(R.sub.b), --N(R.sub.b)C(O)R.sub.a,
--N(R.sub.b)C(O)N(R.sub.a)(R.sub.b),
--N(R.sub.b)S(O).sub.2N(R.sub.a)(R.sub.b), --C(O)OR.sub.a,
--C(O)R.sub.a, --C(O)N(R.sub.b), -alkylenyl-OR.sub.a,
-alkylenyl-OC(O)R.sub.a, -alkylenyl-SR.sub.a,
-alkylenyl-5(O).sub.2R.sub.a, -alkylenyl-S(O).sub.2N(R.sub.b),
-alkylenyl-S(O).sub.2OR.sub.a, -alkylenyl-N(R.sub.1)(R.sub.b),
-alkylenyl-N(R.sub.b)C(O)R.sub.a,
-alkylenyl-N(R.sub.b)C(O)N(R.sub.a)(R.sub.b),
-alkylenyl-N(R.sub.b)S(O).sub.2N(R.sub.a)(R.sub.b),
-alkylenyl-C(O)R.sub.a, -alkylenyl-C(O)R.sub.a,
-alkylenyl-C(O)N(R.sub.a)(R.sub.b), --R.sub.8 and
-alkylenyl-R.sub.8; R.sub.a at each occurrence is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
--R.sub.8, and -alkylenyl-R.sub.8; R.sub.b at each occurrence is
independently selected from the group consisting of hydrogen, alkyl
and haloalkyl; alternatively, R.sub.a and R.sub.b together with the
nitrogen atom to which they are attached form a heterocycle ring
substituted with 0, 1, 2, 3, 4 or 5 substituents independently
selected from the group consisting of halogen, alkyl and haloalkyl;
R.sub.9 at each occurrence is independently selected from the group
consisting of hydrogen, alkyl, --C(O)alkyl, and
--S(O).sub.2(alkyl); R.sub.9 at each occurrence is independently
selected from the group consisting of halogen, alkyl, haloalkyl,
hydroxyalkyl, alkoxyalkyl and haloalkoxyalkyl; and n is, 1, 2, or
3.
2. The method of claim 1, wherein the disorder is selected from the
group of neuropathic pain, allodynia, inflammatory pain,
inflammatory hyperalgesia, bladder overactivity, and urinary
incontinence.
3. A method of treating bladder overactivity in a host mammal in
need of such treatment comprising administering a therapeutically
effective amount of a compound of formula (I) according to claim 1,
or a pharmaceutically acceptable salt thereof.
4. A method of treating urinary incontinence in a host mammal in
need of such treatment comprising administering a therapeutically
effective amount of a compound of formula (I) according to claim 1,
or a pharmaceutically acceptable salt thereof.
5. A method of treating inflammatory pain in a host mammal in need
of such treatment comprising administering a therapeutically
effective amount of a compound of formula (I) according to claim 1,
or a pharmaceutically acceptable salt thereof.
6. A method of treating thermal hyperalgesia in a host mammal in
need of such treatment comprising administering a therapeutically
effective amount of a compound of formula (I) according to claim 1,
or a pharmaceutically acceptable salt thereof.
Description
FIELD OF INVENTION
The present invention relates to compounds of formula (I), which
are useful for treating disorders caused by or exacerbated by
vanilloid receptor activity. The present invention also includes
pharmaceutical compositions containing compounds of formula (I) and
methods for treating pain, bladder overactivity, and urinary
incontinence using said compounds and said pharmaceutical
compositions.
BACKGROUND OF INVENTION
Nociceptors are primary sensory afferent (C and A.delta. fibers)
neurons that are activated by a wide variety of noxious stimuli
including chemical, mechanical, thermal, and proton (pH<6)
modalities. The lipophillic vanilloid, capsaicin, activates primary
sensory fibers via a specific cell surface capsaicin receptor,
cloned as VR1. The intradermal administration of capsaicin is
characterized by an initial burning or hot sensation followed by a
prolonged period of analgesia. The analgesic component of VR1
receptor activation is thought to be mediated by a
capsaicin-induced desensitization of the primary sensory afferent
terminal. Thus, the long lasting anti-nociceptive effects of
capsaicin has prompted the clinical use of capsaicin analogs as
analgesic agents. Further, capsazepine, a capsaicin receptor
antagonist can reduce inflammation-induced hyperalgesia in animal
models. VR1 receptors are also localized on sensory afferents which
innervate the bladder. Capsaicin or resiniferatoxin has been shown
to ameliorate incontinence symptoms upon injection into the
bladder.
The VR1 receptor has been called a "polymodal detector" of noxious
stimuli since it can be activated in several ways. The receptor
channel is activated by capsaicin and other vanilloids and thus is
classified as a ligand-gated ion channel. VR1 receptor activation
by capsaicin can be blocked by the competitive VR1 receptor
antagonist, capsazepine. The channel can also be activated by
protons. Under mildly acidic conditions (pH 6-7), the affinity of
capsaicin for the receptor is increased, whereas at pH<6, direct
activation of the channel occurs. In addition, when membrane
temperature reaches 43.degree. C., the channel is opened. Thus heat
can directly gate the channel in the absence of ligand. The
capsaicin analog, capsazepine, which is a competitive antagonist of
capsaicin, blocks activation of the channel in response to
capsaicin, acid, or heat.
The channel is a nonspecific cation conductor. Both extracellular
sodium and calcium enter through the channel pore, resulting in
cell membrane depolarization. This depolarization increases
neuronal excitability, leading to action potential firing and
transmission of a noxious nerve impulse to the spinal cord. In
addition, depolarization of the peripheral terminal can lead to
release of inflammatory peptides such as, but not limited to,
substance P and CGRP, leading to enhanced peripheral sensitization
of tissue.
Recently, two groups have reported the generation of a "knock-out"
mouse lacking the VR1 receptor. Electrophysiological studies of
sensory neurons (dorsal root ganglia) from these animals revealed a
marked absence of responses evoked by noxious stimuli including
capsaicin, heat, and reduced pH. These animals did not display any
overt signs of behavioral impairment and showed no differences in
responses to acute non-noxious thermal and mechanical stimulation
relative to wild-type mice. The VR1 (-/-) mice also did not show
reduced sensitivity to nerve injury-induced mechanical or thermal
nociception. However, the VR1 knock-out mice were insensitive to
the noxious effects of intradermal capsaicin, exposure to intense
heat (50-55.degree. C.), and failed to develop thermal hyperalgesia
following the intradermal administration of carrageenan.
The compounds of the present invention are novel VR1 antagonists
and have utility in treating pain, pain associated with
inflammatory states, inflammatory thermal hyperalgesia, bladder
overactivity, and urinary incontinence.
SUMMARY OF THE PRESENT INVENTION
The present invention discloses oxazolyl compounds, a method for
inhibiting the VR1 receptor in mammals using these compounds, a
method for controlling pain, pains states associated with
inflammatory states, inflammatory thermal hyperalgesia, bladder
overactivity, and urinary incontinence, in mammals, and
pharmaceutical compositions including those compounds. More
particularly, the present invention is directed to compounds of
formula (I)
##STR00002## or a pharmaceutically acceptable salt, amide, ester,
prodrug, or salt of a prodrug thereof, wherein A is O or
--N(R.sub.3); D is --N(R.sub.4), O or S; R.sub.3 and R.sub.4 are
each independently selected from the group consisting of hydrogen,
alkyl, --C(O)alkyl, and --S(O).sub.2(alkyl); R.sub.1 and R.sub.2
are each independently selected from the group consisting of
hydrogen, alkyl, alkenyl, cyano, nitro, halogen, --OR.sub.5,
--OC(O)R.sub.5, --SR.sub.5, --S(O).sub.2R.sub.5,
--S(O).sub.2OR.sub.5, --S(O).sub.2N(R.sub.5)(R.sub.6),
--N(R.sub.5)(R.sub.6), --N(R.sub.6)C(O)R.sub.5,
--N(R.sub.6)C(O)N(R.sub.5)(R.sub.6),
--N(R.sub.6)S(O).sub.2N(R.sub.5)(R.sub.6), --C(O)R.sub.5,
--C(O)OR.sub.5, --C(O)N(R.sub.5)(R.sub.6), haloalkyl,
-alkylenyl-OR.sub.5, -alkylenyl-OC(O)R.sub.5, -alkylenyl-SR.sub.5,
-alkylenyl-S(O).sub.2R.sub.5, -alkylenyl-S(O).sub.2OR.sub.5,
-alkylenyl-S(O).sub.2N(R.sub.5)(R.sub.6),
-alkylenyl-N(R.sub.5)(R.sub.6), -alkylenyl-N(R.sub.6)C(O)R.sub.5,
-alkylenyl-N(R.sub.6)C(O)N(R.sub.5)(R.sub.6),
-alkylenyl-N(R.sub.6)S(O).sub.2N(R.sub.5)(R.sub.6),
-alkylenyl-C(O)R.sub.5, -alkylenyl-C(O)OR.sub.5,
-alkylenyl-C(O)N(R.sub.5)(R.sub.6), --R.sub.7, and
-alkylenyl-R.sub.7; provided that when one of R.sub.1 and R.sub.2
is hydrogen, the other is not hydrogen; R.sub.5 at each occurrence
is independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl and benzyl; R.sub.6 at each occurrence is
independently selected from the group consisting of hydrogen and
alkyl; R.sub.7 at each occurrence is independently selected from
the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl
and heteroaryl; wherein each R.sub.7 is independently substituted
with 0, 1, 2, 3, 4 or 5 substituents independently selected from
the group consisting of alkyl, alkenyl, halogen, cyano, nitro,
hydroxy, alkoxy, haloalkoxy, --S(alkyl), --S(O).sub.2(alkyl),
--N(H).sub.2, --N(H)(alkyl), --N(alkyl).sub.2, --N(H)C(O)alkyl,
--C(O)OH, --C(O)Oalkyl, --C(O)NH.sub.2, --C(O)N(H)alkyl,
--C(O)N(alkyl).sub.2, --R.sub.8, cyanoalkyl, haloalkyl,
hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylenyl-S(alkyl),
-alkylenyl-S(O).sub.2(alkyl), -alkylenyl-N(H).sub.2,
-alkylenyl-N(H)(alkyl), -alkylenyl-N(alkyl).sub.2,
-alkylenyl-N(H)C(O)alkyl, -alkylenyl-C(O)OH, -alkylenyl-C(O)Oalkyl,
-alkylenyl-C(O)NH.sub.2, -alkylenyl-C(O)N(H)alkyl,
-alkylenyl-C(O)N(alkyl).sub.2, and -alkylenyl-R.sub.8; R.sub.8 at
each occurrence is independently selected from the group consisting
of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl;
wherein each R.sub.8 is independently substituted with 0, 1, 2, 3,
4 or 5 substituents independently selected from the group
consisting of alkyl, alkenyl, halogen, cyano, nitro, hydroxy,
alkoxy, haloalkoxy, --S(alkyl), --S(O).sub.2(alkyl), --N(H).sub.2,
--N(H)(alkyl), --N(alkyl).sub.2, --N(H)C(O)alkyl, --C(O)OH,
--C(O)Oalkyl, --C(O)NH.sub.2, --C(O)N(H)alkyl,
--C(O)N(alkyl).sub.2, cyanoalkyl, haloalkyl, hydroxyalkyl,
alkoxyalkyl, haloalkoxyalkyl, -alkylenyl-S(alkyl),
-alkylenyl-S(O).sub.2(alkyl), -alkylenyl-N(H).sub.2,
-alkylenyl-N(H)(alkyl), -alkylenyl-N(alkyl).sub.2,
-alkylenyl-N(H)C(O)alkyl, -alkylenyl-C(O)OH, -alkylenyl-C(O)Oalkyl,
-alkylenyl-C(O)NH.sub.2, -alkylenyl-C(O)N(H)alkyl, and
-alkylenyl-C(O)N(alkyl).sub.2; W and Y are each independently
selected from the group consisting of --C(R.sub.x)(R.sub.y)-- and
--N(R.sub.z)--; provided that when one of W and Y is
--N(R.sub.z)--, then the other is --C(R.sub.x)(R.sub.y)--; X is
selected from the group consisting of --C(O)--,
--C(R.sub.x)(R.sub.y)--, --N(R.sub.x),
--C(R.sub.x)(R.sub.y)--C(R.sub.x)(R.sub.y)--,
--C(O)--C(R.sub.x)(R.sub.y)--, --C(R.sub.x)(R.sub.y)--C(O)--,
--C(R.sub.x)(R.sub.y)--N(R.sub.z)-- and
--N(R.sub.z)--C(R.sub.x)(R.sub.y)--; provide that when one of W and
Y is --N(R.sub.z)--, then X is selected from the group consisting
of --C(R.sub.x)(R.sub.y)-- and
--C(R.sub.x)(R.sub.y)--C(R.sub.x)(R.sub.y)--; R.sub.x and R.sub.y
at each occurrence are each independently selected from the group
consisting of hydrogen, alkyl, haloalkyl, --OR.sub.a,
--OC(O)R.sub.a, --SR.sub.a, --S(O).sub.2R.sub.a,
--S(O).sub.2N(R.sub.a)(R.sub.b), --S(O).sub.2OR.sub.a,
--N(R.sub.a)(R.sub.b), --N(R.sub.b)C(O)R.sub.a,
--N(R.sub.b)C(O)N(R.sub.a)(R.sub.b),
--N(R.sub.b)S(O).sub.2N(R.sub.a)(R.sub.b), --C(O)OR.sub.a,
--C(O)R.sub.a, --C(O)N(R.sub.a)(R.sub.b), -alkylenyl-OR.sub.a,
-alkylenyl-OC(O)R.sub.a, -alkylenyl-SR.sub.a,
-alkylenyl-S(O).sub.2R.sub.a,
-alkylenyl-S(O).sub.2N(R.sub.a)(R.sub.b),
-alkylenyl-S(O).sub.2OR.sub.a, -alkylenyl-N(R.sub.a)(R.sub.b),
-alkylenyl-N(R.sub.b)C(O)R.sub.a,
-alkylenyl-N(R.sub.b)C(O)N(R.sub.a)(R.sub.b),
-alkylenyl-N(R.sub.b)S(O).sub.2N(R.sub.a)(R.sub.b),
-alkylenyl-C(O)OR.sub.a, -alkylenyl-C(O)R.sub.a,
-alkylenyl-C(O)N(R.sub.a)(R.sub.b), --R.sub.8 and
-alkylenyl-R.sub.8; R.sub.a at each occurrence is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
--R.sub.8 and -alkylenyl-R.sub.8; R.sub.b at each occurrence is
independently selected from the group consisting of hydrogen, alkyl
and haloalkyl; alternatively, R.sub.a and R.sub.b together with the
nitrogen atom to which they are attached form a heterocycle ring
substituted with 0, 1, 2, 3, 4 or 5 substituents independently
selected from the group consisting of halogen, alkyl and haloalkyl;
R.sub.z at each occurrence is independently selected from the group
consisting of hydrogen, alkyl, --C(O)alkyl, and
--S(O).sub.2(alkyl); R.sub.9 at each occurrence is independently
selected from the group consisting of halogen, alkyl, haloalkyl,
hydroxyalkyl, alkoxyalkyl and haloalkoxyalkyl; and n is, 1, 2, or
3.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
As used throughout this specification and the appended claims, the
following terms have the following meanings:
The term "alkenyl" as used herein, means a straight or branched
chain hydrocarbon containing from 2 to 10 carbon atoms and at least
one carbon-carbon double bond. Examples of alkenyl include, but not
limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,
4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and
3-decenyl.
The term "alkyl" as used herein, means a straight or branched chain
hydrocarbon containing from 1 to 10 carbon atoms. Representative
examples of alkyl include, but are not limited to, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,
n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
The term "alkylenyl" or "alkylene" as used herein, means a divalent
group derived from a straight or branched chain hydrocarbon of from
1 to 10 carbon atoms. Representative examples of alkylene or
alkylenyl include, but are not limited to, --CH.sub.2--,
--CH(CH.sub.3)--, --C(CH.sub.3).sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
and --CH.sub.2CH(CH.sub.3)CH.sub.2--
The term "alkoxy" as used herein, means an alkyl group, as defined
herein, appended to the parent molecular moiety through an oxygen
atom. Representative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy.
The term "alkoxyalkyl" as used herein, means an alkoxy group, as
defined herein, appended to the parent molecular moiety through an
alkyl group, as defined herein. Representative examples of
alkoxyalkyl include, but not limited to, methoxymethyl,
methoxyethyl, and ethoxyethyl.
The term "aryl" as used herein, means a phenyl group, or a bicyclic
or a tricyclic hydrocarbon fused ring system containing zero
heteroatom wherein one or more of the fused rings is a phenyl
group. Bicyclic hydrocarbon fused ring systems are exemplified by a
phenyl group fused to a monocyclic cycloalkyl group, as defined
herein, a monocyclic cycloalkenyl group, as defined herein, or
another phenyl group. Tricyclic hydrocarbon fused ring systems are
exemplified by the bicyclic fused hydrocarbon ring system as
defined hereinabove, fused to a monocyclic cycloalkyl group, as
defined herein, a monocyclic cycloalkenyl group, as defined herein,
or another phenyl group. The aryl groups of the present invention
are appended to the parent moiety through any substitutable atoms
in the group. The aryl groups of the present invention can be
unsubstituted or substituted. Representative examples of aryl
include, but are not limited to, phenyl, anthracenyl, naphthyl,
fluorenyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-4-yl,
inden-1-yl, inden-4-yl, naphthyl, phenyl,
5,6,7,8-tetrahydronaphthalen-1-yl,
1,2,3,4-tetrahydronaphthalen-2-yl and tetrahydronaphthyl.
The term "arylalkyl" as used herein, refers to an aryl group, as
used herein, appended to the parent moiety through an alkyl group
as defined herein.
The term "cyano" as used herein, refers to --CN.
The term "cyanoalkyl" as used herein, refers to an alkyl group as
defined herein, in which one or two hydrogen atoms are replaced by
cyano. Representative examples of cyanoalkyl include, but are not
limited to, 1-methyl-1-cyanoethyl and cyanoethyl.
The term "cycloalkyl" or "cycloalkane" as used herein, refers to a
monocyclic, bicyclic or tricyclic saturated hydrocarbon ring system
having zero heteroatom. The monocyclic ring system has three to
eight carbon atoms and zero heteroatom. Examples of monocyclic ring
systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl. The monocyclic cycloalkyl of the
present invention may contain one or two bridges. The term "bridge"
refers to a connection between two of the non-adjacent carbon atoms
connected by an alkylene bridge between one and three additional
carbon atoms. Representative examples of monocyclic cycloalkyl that
contain such bridge or bridges include, but are not limited to,
bicyclo[2.2.1]heptan-1-yl, bicyclo[2.2.1]heptan-2-yl,
bicyclo[2.2.1]heptan-1-yl, bicyclo[3.1.1]heptan-6-yl,
bicyclo[2.2.2]octan-1-yl and adamantyl. The term "cycloalkyl" of
the present invention also include a bicyclic cycloalkyl or
tricyclic cycloalkyl. The bicyclic cycloalkyl of the present
invention refers to a monocyclic cycloalkyl ring fused to another
monocyclic cycloalkyl group, as defined herein. Representative
examples of the bicyclic cycloalkyl include, but are not limited
to, 4a(2H)decahydronaphthalenyl. The bicyclic cycloalkyl groups of
the present invention may have two of the non-adjacent carbon atoms
connected by an alkylene bridge between one and three additional
carbon atoms. Representative examples of the bicyclic cycloalkyl
groups that contain such connection between two non-adjacent carbon
atoms include, but not limited to, octahydro-2,5-methanopentalenyl.
The tricyclic cycloalkyl group of the present invention refers to a
bicyclic cycloalkyl ring, as defined hereinabove, fused to another
monocyclic cycloalkyl group, as defined herein. Representative
example of the tricyclic cycloalkyl group includes, but is not
limited to, dodecahydro-1H-fluoren-9-yl. The monocyclic, bicyclic
and tricyclic cycloalkyl groups of the present invention can be
unsubstituted or substituted, and are connected to the parent
molecular moiety through any substitutable carbon atom of the
group.
The term "cycloalkenyl" or "cycloalkene" as used herein, refers to
a non-aromatic, partially unsaturated, monocyclic or bicyclic
hydrocarbon ring system having zero heteroatom. The monocyclic ring
systems have 4, 5, 6, 7 or 8 carbon atoms and at least one
carbon-carbon double bond. The 4-membered ring systems have one
double bond, the 5- or 6-membered ring systems have one or two
double bonds, and the 7- or 8-membered ring systems have one, two
or three double bonds. Representative examples of cycloalkenyl
groups include, but not limited to, cyclobutenyl, cyclopentenyl,
cyclohexenyl, cycloheptenyl and cyclooctenyl. The term
"cycloalkenyl" of the present invention also include a bicyclic
fused ring system wherein the monocyclic cycloalkenyl ring is fused
to a monocyclic cycloalkyl group, as defined herein, or another
monocyclic cycloalkenyl group, as defined herein. Representative
examples of the bicyclic cycloalkenyl groups include, but not
limited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl
and 1,6-dihydro-pentalene. The cycloalkenyl groups of the present
invention can be unsubstituted or substituted, and are attached to
the parent molecular moiety through any substitutable carbon atom
of the group.
The term "halo" or "halogen" as used herein, means --Cl, --Br, --I
or --F.
The term "haloalkoxy" as used herein, refers to an alkoxy group, as
defined herein, in which one, two, three, four, five or six
hydrogen atoms are replaced by halogen. Representative examples of
haloalkoxy include, but are not limited to, chloromethoxy,
2-fluoroethoxy, trifluoromethoxy, hexafluoroethoxy,
2-chloro-3-fluoropentyloxy, and pentafluoroethoxy.
The term "haloalkoxyalkyl" as used herein, refers to a haloalkoxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Examples of
haloalkoxyalkyl include, but not limited to,
trifluoromethoxymethyl.
The term "haloalkyl" as used herein, refers to an alkyl group, as
defined herein, in which one, two, three or four, five or six
hydrogen atoms are replaced by halogen. Representative examples of
haloalkyl include, but are not limited to, chloromethyl,
2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and
2-chloro-3-fluoropentyl.
The term "heterocycle" or "heterocyclic" as used herein, refers to
a monocyclic or bicyclic, non-aromatic, saturated or partially
unsaturated ring system. Monocyclic ring systems are exemplified by
a 4-membered ring containing one heteroatom independently selected
from oxygen, nitrogen and sulfur; or a 5-, 6-, 7-, or 8-membered
ring containing one, two or three heteroatoms wherein the
heteroatoms are independently selected from nitrogen, oxygen and
sulfur. The 5-membered ring has 0 or 1 double bond. The 6-membered
ring has 0, 1 or 2 double bonds. The 7- or 8-membered ring has 0,
1, 2 or 3 double bonds. Representative examples of monocyclic ring
systems include, but are not limited to, azetidinyl, azepanyl,
azepinyl, diazepinyl, dioxolanyl, dioxanyl, dithianyl,
imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,
isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl,
oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,
piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,
pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl,
tetrahydropyridyl, tetrahydrothienyl, thiadiazolinyl,
thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,
1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl,
1,4-diazepanyl and trithianyl. Bicyclic ring systems are
exemplified by any of the above monocyclic ring systems fused to a
phenyl group, a monocyclic cycloalkenyl group, as defined herein, a
monocyclic cycloalkyl group, as defined herein, or an additional
monocyclic heterocycle group, as defined herein. Representative
examples of bicyclic ring systems include but are not limited to,
benzodioxinyl, benzodioxolyl, benzopyranyl, benzothiopyranyl,
2,3-dihydroindolyl, indolizinyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, 3-azabicyclo[3.2.0]heptyl,
3,6-diazabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrolyl,
hexahydro-1H-furo[3,4-c]pyrrolyl, and
octahydropyrrolo[3,4-c]pyrrolyl. The monocyclic or bicyclic ring
systems as defined herein may have two of the non-adjacent carbon
atoms connected by a heteroatom selected from nitrogen, oxygen or
sulfur, or by an alkylene bridge of between one and three
additional carbon atoms. Representative examples of monocyclic or
bicyclic ring systems that contain such connection between two
non-adjacent carbon atoms include, but not limited to,
2-azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.2]octyl,
2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.1]heptyl,
2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl,
2-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl,
3-azabicyclo[3.1.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl,
8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-8-yl,
3-oxa-8-azabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl,
3,10-diazabicyclo[4.3.1]decyl, or 8-oxa-3-azabicyclo[3.2.1]octyl,
octahydro-1H-4,7-methanoisoindolyl, and
octahydro-1H-4,7-epoxyisoindolyl. The heterocycle groups of the
invention are substituted or unsubstituted, and are connected to
the parent molecular moiety through any substitutable carbon or
nitrogen atom in the groups. The nitrogen heteroatom may or may not
be quaternized, and the nitrogen or sulfur heteroatom may or may
not be oxidized. In addition, the nitrogen containing heterocyclic
rings may or may not be N-protected.
The term "heteroaryl" as used herein, refers to monocyclic or
bicyclic aromatic ring systems where at least one atom is selected
from the group consisting of N, O, and S, and the remaining atoms
are carbon. The monocyclic heteroaryl groups have five or
six-membered rings containing at least one heteroatom selected from
N, O or S and the remainings are carbon. The five membered rings
have two double bonds, and the six membered rings have three double
bonds. The term "heteroaryl" also includes bicyclic heteroaryl
groups where the monocyclic heteroaryl ring, as defined herein, is
fused to a phenyl group, a monocyclic cycloalkyl group, as defined
herein, a monocyclic cycloalkenyl group, as defined herein, a
monocyclic heterocycle group, as defined herein, or an additional
monocyclic heteroaryl group. Representative examples of the
monocyclic and bicyclic heteroaryl groups include, but not limited
to, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl,
6,7-dihydro-1,3-benzothiazolyl, furyl, imidazolyl,
imidazo[1,2-a]pyridinyl, indazolyl, indolyl, isoindolyl,
isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,
oxadiazolyl, oxazolyl, pyridoimidazolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl,
thienyl, triazolyl, thiadiazolyl, tetrazolyl,
1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl, and
5,6,7,8-tetrahydroquinolin-5-yl. The heteroaryl groups of the
present invention can be substituted or unsubstituted, and are
connected to the parent molecular moiety through any substitutable
carbon or nitrogen atom in the groups. In addition, the nitrogen
heteroatom may or may not be quaternized, the nitrogen and the
sulfur atoms in the group may or may not be oxidized. Also, the
nitrogen containing rings may or may not be N-protected.
The term "heteroatom" as used herein, refers to nitrogen, oxygen or
sulfur atom.
The term "hydroxy" or "hydroxyl" as used herein, means an --OH
group.
The term "hydroxyalkyl" as used herein, refers to an alkyl group,
as defined herein, in which one or two hydrogen atoms are replaced
by a hydroxyl group, as defined herein. Representative examples of
hydroxyalkyl include, but are not limited to, hydroxymethyl,
2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and
2-ethyl-4-hydroxyheptyl.
The term "nitro" as used herein, means --NO.sub.2
Compounds of the Present Invention
2. Compounds of the invention can have the formula (I) as described
above. More particularly, compounds of formula (I) can include, but
are not limited to compounds wherein D is --N(R.sub.4) and A is O.
Compounds of the invention can include those wherein D is
--N(R.sub.4) and A is --N(R.sub.3) Other compounds of the invention
include those in which A is O and D is S.( ) Other compounds
included in the present invention may be those in which D is S and
A is --N(R.sub.3). Preferred compounds are those in which D is S
and A is --N(R.sub.3), R.sub.1 is hydrogen; R.sub.2 is --R.sub.7;
R.sub.3 is hydrogen; R.sub.7 is phenyl; W is --C(R.sub.x)(R.sub.y);
Y is --C(R.sub.x)(R.sub.y); X is
--C(R.sub.x)(R.sub.y)--C(R.sub.x)(R.sub.y)--; R.sub.x is
--O(R.sub.a), and R.sub.y is hydrogen. Other compounds of the
present invention comprise those in which both D and A are O.
Compounds of the invention can include those wherein D is O, A is
--N(R.sub.3), wherein R.sub.3 is hydrogen Preferred compounds are
those in which D is O, A is --N(R.sub.3), R.sub.3 is hydrogen,
R.sub.1 is hydrogen and R.sub.2 is aryl,) more preferably those in
which R.sub.2 is phenyl. These preferred compounds include those in
which W is --C(R.sub.x)(R.sub.y), Y is --C(R.sub.x)(R.sub.y), and X
is --C(O)--C(R.sub.x)(R.sub.y)--, wherein R.sub.x and R.sub.y are
hydrogen Other compounds comprised are those in which R.sub.2 is
phenyl, W is --C(R.sub.x)(R.sub.y), Y is --C(R.sub.x)(R.sub.y), and
X is --C(R.sub.x)(R.sub.y)--C(R.sub.x)(R.sub.y)--; preferably those
in which R.sub.x is --OH and R.sub.y is hydrogen. Also, preferred
compounds include those in which R.sub.x is --N(R.sub.a)(R.sub.b),
and R.sub.a and R.sub.b are hydrogen. and those in which R.sub.x is
--N(R.sub.a)(R.sub.b), R.sub.a is --S(O).sub.2(alkyl), and R.sub.b
is hydrogen.
Other compounds of the present invention include those in which D
is O, A is --N(R.sub.3), wherein R.sub.3 is hydrogen, R.sub.1 is
hydrogen, and R.sub.2 is cycloalkyl. Preferably those in which W is
--C(R.sub.x)(R.sub.y), Y is --C(R.sub.x)(R.sub.y), and X is
--C(O)--C(R.sub.x)(R.sub.y)--, wherein R.sub.x and R.sub.y are
hydrogen. Other compounds include those in which D is O, A is
--N(R.sub.3), wherein R.sub.3 is hydrogen, R.sub.1 is hydrogen,
R.sub.2 is cycloalkyl, W is --C(R.sub.x)(R.sub.y), Y is
--C(R.sub.x)(R.sub.y), and X is
--C(R.sub.x)(R.sub.y)--C(R.sub.x)(R.sub.y)--, preferably those in
which R.sub.x is --OH and R.sub.y is hydrogen. Other compounds of
the present invention include those in which D is O, A is
--N(R.sub.3), wherein R.sub.3 is hydrogen, R.sub.1 is hydrogen, and
R.sub.2 is alkyl, preferably those in which W is
--C(R.sub.x)(R.sub.y), Y is --C(R.sub.x)(R.sub.y), and X is
--C(O)--C(R.sub.x)(R.sub.y)--, wherein R.sub.x and R.sub.y are
hydrogen Other preferred compounds include those in which D is O, A
is --N(R.sub.3), wherein R.sub.3 is hydrogen, R.sub.1 is hydrogen,
R.sub.2 is alkyl, W is --C(R.sub.x)(R.sub.y), Y is
--C(R.sub.x)(R.sub.y), and X is
--C(R.sub.x)(R.sub.y)--C(R.sub.x)(R.sub.y)--, preferably those in
which R.sub.x is --OH and R.sub.y is hydrogen. The present
invention also includes compounds in which D is O, A is
--N(R.sub.3), wherein R.sub.3 is hydrogen, R.sub.1 is hydrogen,
R.sub.2 is alkyl-R.sub.7. Preferred compounds are those in which
R.sub.7 is phenyl, W is --C(R.sub.x)(R.sub.y), Y is
--C(R.sub.x)(R.sub.y), and X is --C(O)--C(R.sub.x)(R.sub.y)--,
wherein R.sub.x and R.sub.y are hydrogen. Other compounds included
in the present invention are those in which D is O, A is
--N(R.sub.3), wherein R.sub.3 is hydrogen, R.sub.1 is hydrogen,
R.sub.2 is alkyl-R.sub.7, R.sub.7 is phenyl, W is
--C(R.sub.x)(R.sub.y), Y is --C(R.sub.x)(R.sub.y), and X is
--C(R.sub.x)(R.sub.y)--C(R.sub.x)(R.sub.y)--, preferably those in
which R.sub.x is --OH and R.sub.y is hydrogen. The present
invention also includes compounds wherein D is O, A is
--N(R.sub.3), R.sub.3 is alkyl, W is --C(R.sub.x)(R.sub.y), Y is
--C(R.sub.x)(R.sub.y), and X is --C(O)--C(R.sub.x)(R.sub.y)--,
wherein R.sub.x and R.sub.y are hydrogen. Other included compounds
are those in which D is O, A is --N(R.sub.3), R.sub.3 is
--C(O)alkyl, W is --C(R.sub.x)(R.sub.y), Y is
--C(R.sub.x)(R.sub.y), and X is --C(O)--C(R.sub.x)(R.sub.y)--,
wherein R.sub.x and R.sub.y are hydrogen, and those in which D is
O, A is --N(R.sub.3), R.sub.3 is --C(O)alkyl, W is
--C(R.sub.x)(R.sub.y), Y is --C(R.sub.x)(R.sub.y), and X is
--C(R.sub.x)(R.sub.y)--C(R.sub.x)(R.sub.y)--, preferably those in
which R.sub.x is --OH and R.sub.y is hydrogen. The present
invention also includes pharmaceutical compositions comprising
therapeutically effective amounts of a compound with a formula (I)
as described above, or a pharmaceutically acceptable salt, amide,
ester or prodrug thereof.
Preparation of Compounds of the Present Invention
The compounds of this invention can be prepared by a variety of
synthetic procedures. Representative procedures are shown in, but
are not limited to, Schemes 1-5.
##STR00003##
Compounds of formula (3) wherein W, X, Y, R.sub.1, R.sub.2, R.sub.9
and n are as defined in formula (I) can be prepared as shown in
Scheme 1. Amines of formula (I), either purchased or prepared using
methodologies known to one skilled in the art, can be converted to
isothiocyanates of formula (2) by reacting with reagents such as,
but not limited to, O,O-dipyridin-2-yl-thiocarbonate, thiophosgene,
thiourea/HCl or CS.sub.2/aqueous NH.sub.3. Reaction of the
isothiocyanates of formula (2) with azides of formula (5), followed
by spontaneous ring closure provides oxazoles of formula (3). The
reaction is generally performed in the presence of
triphenylphosphine or tributylphosphine in a solvent such as, but
not limited to, dichloromethane or dioxane, at a temperature from
about room temperature to about 100.degree. C.
Azides of formula (5) can be purchased or prepared from compounds
of formula (4) wherein X.sub.b is I, Cl, Br, mesylate or tosylate
by reacting with sodium azide or trimethylsilylazide in a solvent
such as, but not limited to, acetone, N,N-dimethylformamide,
ethanol, dimethylsulfoxide, or hexamethylphosphoramide, at a
temperature from about room temperature to about 100.degree. C.
##STR00004##
Imidazoles of formula (9) wherein R.sub.1, R.sub.2, R.sub.9, n, W,
X, Y and R.sub.4 are as defined in formula (I) can be prepared as
shown in Scheme 2. Amines of formula (1) can be converted to
guanidines of formula (8) using a reagent such as, but not limited
to, nitrosoguanidine/HCl, cyanamide/HCl or reagent of formula (6)
wherein R.sub.101 is tert-butoxycarbonyl or benzyloxycarbonyl. In
the case of where reagents of formula (6) is used, deprotection of
the guanidine using methodologies known to one skilled in organic
synthesis, transforms compounds of formula (7) wherein R.sub.102 is
tert-butoxycarbonyl or benzyloxycarbonyl to compounds of formula
(7) wherein R.sub.102 is hydrogen. Reaction of guanidines of
formula (7) wherein R.sub.102 is hydrogen with compounds of formula
(8) wherein X.sub.a is a leaving group such as, but not limited to,
Cl, Br, I, triflate or methanesulfonate, (prepared from the
corresponding alcohols using synthetic routes known to one skilled
in the art) followed by spontaneous ring closure, provides
imidazoles of formula (9) wherein R.sub.4 is hydrogen.
Imidazoles of formula (9) wherein R.sub.4 is hydrogen can be
converted to compounds of formula (9) wherein R.sub.4 is alkyl by
reaction with alkyl halides of formula R.sub.4X wherein X is Br, Cl
or I in the presence of a base such as, but not limited to, sodium
hydride.
Imidazoles of formula (9) wherein R.sub.4 is hydrogen can be
converted to compounds of formula (9) wherein R.sub.4 is
--C(O)alkyl by reaction with acyl halides of formula alkylC(O)X
wherein X is Cl, Br or I, or anhydrides of formula
(R.sub.4CO).sub.2O wherein R.sub.4 is alkyl, in the presence of a
base such as triethylamine.
Imidazoles of formula (9) wherein R.sub.4 is hydrogen can be
converted to compounds of formula (9) wherein R.sub.4 is
--S(O).sub.2alkyl by reaction with compounds of formula
alkylS(O).sub.2X wherein X is Cl, Br or I in the presence of a base
such as triethylamine.
##STR00005##
Thiazoles of formula (11) wherein W, X, Y, R.sub.1, R.sub.2,
R.sub.9 and n are as defined in formula (I), can be prepared from
isothiocyanates of formula (2) as depicted in Scheme 3. Reaction of
isothiocyanates of formula (2) with gaseous ammonia in a solvent
such as, but not limited to, dioxane or tetrahydrofuran, at about
room temperature provides thioureas of formula (10). Conversion of
thioureas of formula (10) to thiazoles of formula (11) can be
effected using similar reaction conditions employed for the
transformation of compounds of formula (7) to imidazoles of formula
(9).
##STR00006##
Compounds of formula (15) wherein D, R.sub.1, R.sub.2, R.sub.8,
R.sub.9 and n are as defined in formula (I), and G is selected from
the group consisting of cyclopentane, cyclohexane, piperidine and
pyrrolidine, and each ring G is independently unsubstituted or
substituted with substituents as described in --W--X--Y-- of
formula (I), can be prepared as shown in Scheme 4.
Alcohols of formula (12) wherein R.sub.104 is --OH and R.sub.103 is
NO.sub.2 or --N(H)(R.sub.105) wherein R.sub.105 is a nitrogen
protecting group, can be converted to compounds of formula (13) by
reacting with compounds of formula R.sub.8X, wherein R.sub.c is
triflate, Br or I, in the presence of a metal catalyst, a ligand,
and a base. The reaction is generally conducted in a solvent such
as, but not limited to, dioxane, toluene, N,N-dimethylformamide
(DMF), N,N-dimethylacetamide, N-methylpyrrolidinone (NMP) or
pyridine. Examples of metal catalysts include, but not limited to,
palladium diacetate and tris(dibenzylideneacetone)dipalladium(0).
Examples of ligands include, but not limited to,
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and
tri-tertbutylphosphine. Examples of bases include, but not limited
to, sodium tert-butoxide, sodium hydride, and cesium carbonate.
Alternatively, compounds of formula (13) wherein R.sub.103 is
NO.sub.2 or --N(H)(R.sub.105) and R.sub.105 is a nitrogen
protecting group can be made from the reaction of formula (12)
wherein R.sub.104 is triflate, Br or I, and R.sub.103 is NO.sub.2
or --N(H)(R.sub.105) wherein R.sub.105 is a nitrogen protecting
group, with alcohols of formula R.sub.8OH using the reaction
conditions as described in the preceding paragraph.
Conversion of certain alcohols of formula (12) wherein R.sub.104 is
--OH and R.sub.103 is NO.sub.2 or --N(H)(R.sub.105) wherein
R.sub.105 is a nitrogen protecting group, to compounds of formula
(13) can also be achieved by reaction with alcohols of formula
R.sub.8OH in the presence of diethylazodicarboxylate or
di-(tert-butyl)azodicarboxylate and triphenyl phosphine, a
condition known as Mitsunobo reaction.
Subsequently, compounds of formula (13) wherein R.sub.103 is
N(H)(R.sub.105) and R.sub.105 is a nitrogen protecting group can be
converted to compounds of formula (14) by reaction with a suitable
deprotecting reagent known to one skilled in the art. Compounds of
formula (13) wherein R.sub.103 is NO.sub.2 can be reduced to
compounds of formula (14) using a reducing agent. Examples of
reducing agents include, but not limited to, lithium aluminium
hydride or tin (or zinc or iron)/HCl. The transformation can also
be effected by hydrogen in the presence of a catalyst, such as, but
not limited to, palladium on carbon or palladium hydroxide on
carbon.
Compounds of formula (14) can be converted to compounds of formula
(15) using the reaction conditions as described in schemes 1, 2,
and 3.
##STR00007##
Alternatively, compounds of formula (15) wherein D, R.sub.1,
R.sub.2, R.sub.8, R.sub.9 and n are as defined in formula (I), G is
selected from the group consisting of cyclopentane, cyclohexane,
piperidine and pyrrolidine and each G is independently
unsubstituted or substituted with substituents as described in
--W--X--Y-- of formula (I), can be prepared from compounds of
formula (16) wherein R.sub.104 is halogen, triflate or --OH (either
purchased or prepared using transformations as described in schemes
1, 2 and 3) using reaction conditions for the transformation of
compounds of formula (12) to compounds of formula (13) as described
in Scheme 4.
##STR00008##
Compounds of formula (19) wherein A, W, X, Y, D, R.sub.1, R.sub.2,
R.sub.9 and n are as defined in formula (I), can be prepared as
shown in Scheme 6.
Compounds of formula (17) wherein R.sub.106 is triflate, Br or I,
can be reacted with compounds of formula (18) wherein R.sub.107 is
NH.sub.2 or OH, in the presence of a ligand, a metal catalyst and a
base as shown in Scheme 4, to provide compounds of formula (19)
wherein A is O or NH.
Alternatively, compounds of formula (17) wherein R.sub.106 is
NH.sub.2 or OH, can be reacted with compounds of formula (18)
wherein R.sub.107 is triflate, Br or I, in the presence of a
ligand, a metal catalyst and a base as shown in Scheme 4, to
provide compounds of formula (19) wherein A is O or NH.
Compounds of formula (19) wherein A is O and W, X, Y, D, R.sub.1,
R.sub.2, R.sub.9 and n are as defined in formula (I), can also be
obtained by reacting compounds of formula (17) wherein R.sub.106 is
OH with compounds of formula (18) wherein R.sub.107 is OH using
Mitsunobo conditions.
Compounds of formula (19) wherein A is NH can be converted to
compounds of formula (19) wherein A is N(R.sub.3) wherein R.sub.3
is alkyl, --C(O)alkyl or --S(O).sub.2(alkyl) can be achieved by
reaction with compounds of formula R.sub.3X wherein X is Cl, Br or
I and R.sub.3 is alkyl, --C(O)alkyl or --S(O).sub.2(alkyl) as
described in Scheme 2.
Compounds of formula (19) wherein W, X and Y together with the
carbon atoms form a ring selected from the group consisting of
cyclohexane and piperidine and that each ring is independently
unsubstituted or substituted with substituents as described in
W--X--Y of formula (I) can be either purchased or prepared by known
synthetic routes. One example of such synthesis involves reduction
of compounds of formula (19) wherein W, X and Y together with the
carbon atoms form an unsubstituted or substituted ring selected
from the group consisting of benzene and pyridine, using hydrogen
gas, in the presence of Raney/nickel and sodium hydroxide.
##STR00009##
Compounds of formula (23) wherein D, R.sub.1, R.sub.2, R.sub.8,
R.sub.9 and n are as defined in formula (I), and G is selected from
the group consisting of cyclopentane, cyclohexane, piperidine and
pyrrolidine, and each ring G is independently unsubstituted or
substituted with substituents as described in --W--X--Y-- of
formula (I), can be prepared as shown in scheme 7.
Conversion of certain alcohols of formula (12), wherein R.sub.104
is --OH and R.sub.103 is NO.sub.2 or --N(H)(R.sub.105) wherein
R.sub.105 is a nitrogen protecting group, to compounds of formula
(20), wherein R.sub.108 is a "protected" form of amine such as
azido or phthalimido, can be achieved by activation of the hydroxyl
group through conversion to, for example, a tosylate or mesylate
group followed by reaction with a nitrogen source such as sodium
azide or sodium phthalimide as in the Gabriel synthesis. Compounds
of formula (20) can be converted to compounds of formula (21),
wherein R.sub.109 is hydrogen or a nitrogen protecting group,
through a reduction and protection sequence known to one skilled in
the art. Examples of reducing agents include, but not limited to,
lithium aluminum hydride, hydrazine, and hydrogen in the presence
of a catalyst.
Compounds of formula (22) can be converted to compounds of formula
(23) using the reaction conditions as described in schemes 1, 2,
and 3.
It is understood that the schemes described herein are for
illustrative purposes and that routine experimentation, including
appropriate manipulation of the sequence of the synthetic route,
protection of any chemical functionality that are not compatible
with the reaction conditions and the removal of such protecting
groups are included in the scope of the invention.
Compositions of the Invention
The invention also provides pharmaceutical compositions comprising
a therapeutically effective amount of a compound of formula (I) in
combination with a pharmaceutically acceptable carrier. The
compositions comprise compounds of the invention formulated
together with one or more non-toxic pharmaceutically acceptable
carriers. The pharmaceutical compositions can be formulated for
oral administration in solid or liquid form, for parenteral
injection or for rectal administration.
The term "pharmaceutically acceptable carrier," as used herein,
means a non-toxic, inert solid, semi-solid or liquid filler,
diluent, encapsulating material or formulation auxiliary of any
type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as lactose,
glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; cocoa butter and suppository
waxes; oils such as peanut oil, cottonseed oil, safflower oil,
sesame oil, olive oil, corn oil and soybean oil; glycols; such a
propylene glycol; esters such as ethyl oleate and ethyl laurate;
agar; buffering agents such as magnesium hydroxide and aluminum
hydroxide; alginic acid; pyrogen-free water; isotonic saline;
Ringer's solution; ethyl alcohol, and phosphate buffer solutions,
as well as other non-toxic compatible lubricants such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of one
skilled in the art of formulations.
The pharmaceutical compositions of this invention can be
administered to humans and other mammals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments or drops), bucally or as an
oral or nasal spray. The term "parenterally," as used herein,
refers to modes of administration, including intravenous,
intramuscular, intraperitoneal, intrasternal, subcutaneous,
intraarticular injection and infusion.
Pharmaceutical compositions for parenteral injection comprise
pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents or vehicles include water, ethanol, polyols
(propylene glycol, polyethylene glycol, glycerol, and the like, and
suitable mixtures thereof), vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate, or suitable
mixtures thereof. Suitable fluidity of the composition may be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
These compositions can also contain adjuvants such as preservative
agents, wetting agents, emulsifying agents, and dispersing agents.
Prevention of the action of microorganisms can be ensured by
various antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It also can be
desirable to include isotonic agents, for example, sugars, sodium
chloride and the like. Prolonged absorption of the injectable
pharmaceutical form can be brought about by the use of agents
delaying absorption, for example, aluminum monostearate and
gelatin.
In some cases, in order to prolong the effect of a drug, it is
often desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This can be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug can depend upon its rate of dissolution, which, in turn, may
depend upon crystal size and crystalline form. Alternatively, a
parenterally administered drug form can be administered by
dissolving or suspending the drug in an oil vehicle.
Suspensions, in addition to the active compounds, can contain
suspending agents, for example, ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar,
tragacanth, and mixtures thereof.
If desired, and for more effective distribution, the compounds of
the invention can be incorporated into slow-release or
targeted-delivery systems such as polymer matrices, liposomes, and
microspheres. They may be sterilized, for example, by filtration
through a bacteria-retaining filter or by incorporation of
sterilizing agents in the form of sterile solid compositions, which
may be dissolved in sterile water or some other sterile injectable
medium immediately before use.
Injectable depot forms are made by forming microencapsulated
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides) Depot
injectable formulations also are prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
The injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved or dispersed in sterile water or other sterile
injectable medium just prior to use.
Injectable preparations, for example, sterile injectable aqueous or
oleaginous suspensions can be formulated according to the known art
using suitable dispersing or wetting agents and suspending agents.
The sterile injectable preparation also can be a sterile injectable
solution, suspension or emulsion in a nontoxic, parenterally
acceptable diluent or solvent such as a solution in 1,3-butanediol.
Among the acceptable vehicles and solvents that can be employed are
water, Ringer's solution, U.S.P. and isotonic sodium chloride
solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose any
bland fixed oil can be employed including synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid are used
in the preparation of injectables.
Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
one or more compounds of the invention is mixed with at least one
inert pharmaceutically acceptable carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as
starches, lactose, sucrose, glucose, mannitol, and salicylic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay; and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using lactose or
milk sugar as well as high molecular weight polyethylene
glycols.
The solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteric
coatings and other coatings well-known in the pharmaceutical
formulating art. They can optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract in a delayed manner. Examples of materials useful
for delaying release of the active agent can include polymeric
substances and waxes.
Compositions for rectal or vaginal administration are preferably
suppositories which can be prepared by mixing the compounds of this
invention with suitable non-irritating carriers such as cocoa
butter, polyethylene glycol or a suppository wax which are solid at
ambient temperature but liquid at body temperature and therefore
melt in the rectum or vaginal cavity and release the active
compound.
Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches. A
desired compound of the invention is admixed under sterile
conditions with a pharmaceutically acceptable carrier and any
needed preservatives or buffers as may be required. Ophthalmic
formulation, eardrops, eye ointments, powders and solutions are
also contemplated as being within the scope of this invention. The
ointments, pastes, creams and gels may contain, in addition to an
active compound of this invention, animal and vegetable fats, oils,
waxes, paraffins, starch, tragacanth, cellulose derivatives,
polyethylene glycols, silicones, bentonites, silicic acid, talc and
zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of
this invention, lactose, talc, silicic acid, aluminum hydroxide,
calcium silicates and polyamide powder, or mixtures of these
substances. Sprays can additionally contain customary propellants
such as chlorofluorohydrocarbons.
Compounds of the invention also can be administered in the form of
liposomes. As is known in the art, liposomes are generally derived
from phospholipids or other lipid substances. Liposomes are formed
by mono- or multi-lamellar hydrated liquid crystals that are
dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metabolizable lipid capable of forming liposomes may
be used. The present compositions in liposome form may contain, in
addition to the compounds of the invention, stabilizers,
preservatives, and the like. The preferred lipids are the natural
and synthetic phospholipids and phosphatidylcholines (lecithins)
used separately or together.
Methods to form liposomes are known in the art. See, for example,
Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press,
New York, N.Y., (1976), p 33 et seq.
Dosage forms for topical administration of a compound of this
invention include powders, sprays, ointments and inhalants. The
active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants. Ophthalmic formulations, eye ointments,
powders and solutions are also contemplated as being within the
scope of this invention. Aqueous liquid compositions of the
invention also are particularly useful.
The compounds of the invention can be used in the form of
pharmaceutically acceptable salts, esters, or amides derived from
inorganic or organic acids. The term "pharmaceutically acceptable
salts, esters and amides," as used herein, include salts,
zwitterions, esters and amides of compounds of formula (I) which
are, within the scope of sound medical judgment, suitable for use
in contact with the tissues of humans and lower animals without
undue toxicity, irritation, allergic response, and the like, are
commensurate with a reasonable benefit/risk ratio, and are
effective for their intended use.
The term "pharmaceutically acceptable salt" refers to those salts
which are, within the scope of sound medical judgment, suitable for
use in contact with the tissues of humans and lower animals without
undue toxicity, irritation, allergic response, and the like, and
are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well-known in the art. The
salts can be prepared in situ during the final isolation and
purification of the compounds of the invention or separately by
reacting a free base function with a suitable organic acid.
Representative acid addition salts include, but are not limited to
acetate, adipate, alginate, citrate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate,
maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,
oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate,
picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
phosphate, glutamate, bicarbonate, p-toluenesulfonate and
undecanoate.
Also, the basic nitrogen-containing groups can be quaternized with
such agents as lower alkyl halides such as methyl, ethyl, propyl,
and butyl chlorides, bromides and iodides; dialkyl sulfates such as
dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides
such as decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides; arylalkyl halides such as benzyl and phenethyl bromides
and others. Water or oil-soluble or dispersible products are
thereby obtained.
Examples of acids which can be employed to form pharmaceutically
acceptable acid addition salts include such inorganic acids as
hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric
acid and such organic acids as oxalic acid, maleic acid, succinic
acid, and citric acid.
Basic addition salts can be prepared in situ during the final
isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation or with ammonia or an
organic primary, secondary or tertiary amine. Pharmaceutically
acceptable salts include, but are not limited to, cations based on
alkali metals or alkaline earth metals such as lithium, sodium,
potassium, calcium, magnesium, and aluminum salts, and the like,
and nontoxic quaternary ammonia and amine cations including
ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, diethylamine,
ethylamine and the such as. Other representative organic amines
useful for the formation of base addition salts include
ethylenediamine, ethanolamine, diethanolamine, piperidine, and
piperazine.
The term "pharmaceutically acceptable ester," as used herein,
refers to esters of compounds of the invention which hydrolyze in
vivo and include those that break down readily in the human body to
leave the parent compound or a salt thereof. Examples of
pharmaceutically acceptable, non-toxic esters of the invention
include C.sub.1-to-C.sub.6 alkyl esters and C.sub.5-to-C.sub.7
cycloalkyl esters, although C.sub.1-to-C.sub.4 alkyl esters are
preferred. Esters of the compounds of formula (I) can be prepared
according to conventional methods. Pharmaceutically acceptable
esters can be appended onto hydroxy groups by reaction of the
compound that contains the hydroxy group with acid and an
alkylcarboxylic acid such as acetic acid, or with acid and an
arylcarboxylic acid such as benzoic acid. In the case of compounds
containing carboxylic acid groups, the pharmaceutically acceptable
esters are prepared from compounds containing the carboxylic acid
groups by reaction of the compound with base such as triethylamine
and an alkyl halide, alkyl trifilate, for example with methyl
iodide, benzyl iodide, cyclopentyl iodide. They also can be
prepared by reaction of the compound with an acid such as
hydrochloric acid and an alkylcarboxylic acid such as acetic acid,
or with acid and an arylcarboxylic acid such as benzoic acid.
The term "pharmaceutically acceptable amide," as used herein,
refers to non-toxic amides of the invention derived from ammonia,
primary C.sub.1-to-C.sub.6 alkyl amines and secondary
C.sub.1-to-C.sub.6 dialkyl amines. In the case of secondary amines,
the amine can also be in the form of a 5- or 6-membered heterocycle
containing one nitrogen atom. Amides derived from ammonia,
C.sub.1-to-C.sub.3 alkyl primary amides and C.sub.1-to-C.sub.2
dialkyl secondary amides are preferred. Amides of the compounds of
formula (I) can be prepared according to conventional methods.
Pharmaceutically acceptable amides can be prepared from compounds
containing primary or secondary amine groups by reaction of the
compound that contains the amino group with an alkyl anhydride,
aryl anhydride, acyl halide, or aroyl halide. In the case of
compounds containing carboxylic acid groups, the pharmaceutically
acceptable esters are prepared from compounds containing the
carboxylic acid groups by reaction of the compound with base such
as triethylamine, a dehydrating agent such as dicyclohexyl
carbodiimide or carbonyl diimidazole, and an alkyl amine,
dialkylamine, for example with methylamine, diethylamine,
piperidine. They also can be prepared by reaction of the compound
with an acid such as sulfuric acid and an alkylcarboxylic acid such
as acetic acid, or with acid and an arylcarboxylic acid such as
benzoic acid under dehydrating conditions as with molecular sieves
added. The composition can contain a compound of the invention in
the form of a pharmaceutically acceptable prodrug.
The term "pharmaceutically acceptable prodrug" or "prodrug," as
used herein, represents those prodrugs of the compounds of the
invention which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use. Prodrugs of the invention can be
rapidly transformed in vivo to a parent compound of formula (I),
for example, by hydrolysis in blood. A thorough discussion is
provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery
Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.
Roche, ed., Bioreversible Carriers in Drug Design, American
Pharmaceutical Association and Pergamon Press (1987).
The invention contemplates pharmaceutically active compounds either
chemically synthesized or formed by in vivo biotransformation to
compounds of formula (I).
Methods of the Invention
Compounds and compositions of the invention are useful for
ameliorating or preventing disorders involving VR1 receptor
activation such as, but not limited to, inflammatory thermal
hyperalgesia, bladder overactivity, and urinary incontinence as
described by Nolano, M. et al., Pain, Vol. 81, pages 135-145,
(1999); Caterina, M. J. and Julius, D., Annu. Rev. Neurosci. Vol.
24, pages 487-517 (2001); Caterina, M. J. et al., Science Vol. 288
pages 306-313 (2000); Caterina, M. J. et al., Nature Vol. 389 pages
816-824 (1997); Fowler, C. Urology Vol. 55 pages 60-64 (2000); and
Davis, J. et al., Nature Vol. 405 pages 183-187.
The present invention also provides pharmaceutical compositions
that comprise compounds of the present invention. The
pharmaceutical compositions comprise compounds of the present
invention that may be formulated together with one or more
non-toxic pharmaceutically acceptable carriers.
EXAMPLES
The following Examples are intended as an illustration of and not a
limitation upon the scope of the invention as defined in the
appended claims.
Example 1
8-({5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-3,4-dihydronaphth-
alen-2(1H)-one
Example 1A
2-bromo-1-(4-tert-butylphenyl)ethanone
A solution of 4-tert-butylacetophenone (5 g, 28.4 mmol) in acetic
acid (2 mL) was carefully (the reaction was exothermic) treated
with Br.sub.2 (1.46 mL, 28.5 mmol), followed by 48% aq. HBr (0.015
mL, 0.132 mmol). The reaction was stirred at room temperature for 4
hours, then was poured onto ice and was extracted with diethyl
ether. The organic phase was concentrated and was then
chromatographed on silica gel, eluting with 5% ethyl
acetate-hexane, followed by 10% ethyl acetate-hexane, to afford the
title compound as a pale brown oil, 1.305 g (18%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.94 (d, 2H, J=8.5 Hz), 7.58 (d, 2H, J=8.5
Hz), 4.90 (s, 2H), 1.31 (s, 9H); MS (ESI.sup.+) m/z 255 (M+H).
Example 1B
2-azido-1-(4-tert-butylphenyl)ethanone
To a solution of the product of Example 1A (985 mg, 3.86 mmol) in
45 mL acetone was added NaN.sub.3 (0.505 g, 7.07 mmol), and the
mixture stirred overnight at room temperature. The reaction mixture
was poured into saturated NaCl solution and extracted with
dichloromethane. The extracts were washed with saturated NaCl
solution, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to
afford the title compound as a yellow oil (715 mg, 85%). .sup.1H
NMR (DMSO-d.sub.6) .delta. 7.88 (d, 2H, J=8.5 Hz), 7.57 (d, 2H,
J=8.5 Hz), 4.86 (s, 2H), 1.31 (s, 9H); MS (ESI.sup.+) m/z 218
(M+H).
Example 1C
tert-butyl 7-ethoxy-1-naphthylcarbamate
To 8-amino-2-naphthol (10 g, 62.9 mmol) in 200 mL tetrahydrofuran
was added di-tert-butyl dicarbonate (13.4 g, 62.8 mmol) in 20 mL
tetrahydrofuran, and the reaction mixture was refluxed overnight.
The reaction mixture was cooled to room temperature and
concentrated in vacuo. The residue was dissolved in ethyl acetate,
washed with saturated Na.sub.2CO.sub.3 solution and water, dried
over Na.sub.2SO.sub.4, filtered and concentrated. A solution of the
concentrate in N,N-dimethylformamide (60 mL) was treated with
Cs.sub.2CO.sub.3 (32.2 g, 98.8 mmol) and iodoethane (4.4 mL, 8.46
g, 53.5 mmol), and the mixture was vigorously stirred at 60.degree.
for 3 h. The mixture was then cooled to rt, poured into H.sub.2O,
and extracted with ethyl acetate. The extracts were washed with
H.sub.2O and brine, dried over MgSO.sub.4, filtered, and evaporated
in vacuo to afford the title compound as a brown oil (14.47 g,
80%). .sup.1H NMR (DMSO-d.sub.6) .delta. 9.14 (s, 1H), 7.81 (d, 1H,
8.9 Hz), 7.61 (d, 1H, J=8.2 Hz), 7.54 (d, 1H, 7.8 Hz), 7.37 (d, 1H,
J=2.7 Hz), 7.28 (t, 1H, J=7.8 Hz), 7.15 (dd, 1H, J=8.9 Hz, 2.7 Hz),
4.16 (q, 2H, J=7.1 Hz), 1.50 (s, 9H), 1.09 (t, 3H, J=7.0 Hz); MS
(ESI.sup.+) m/z 310 (M+Na).sup.+.
Example 1D
7-ethoxy-1-naphthylamine
To a solution of the product of Example 1C (14.47 g, 50.4 mmol) in
dioxane (30 mL) at 0.degree. C. was added 4N HCl in dioxane (60 mL,
240 mmol). The reaction mixture was stirred at room temperature for
3.5 hours, diluted with 3 volumes of diethyl ether. The resulting
dark brown precipitate was collected by filtration. It was then
treated with saturated NaHCO.sub.3 solution and was extracted with
ethyl acetate. The solution was dried over MgSO.sub.4, filtered and
evaporated in vacuo to yield the title compound (4.88 g, 52%).
Example 1E
7-ethoxy-5,8-dihydronaphthalen-1-amine
The product of Example 1D (1.8 g, 9.63 mmol) and tert-butanol (2.13
g, 28.8 mmol) were dissolved in tetrahydrofuran (20 mL) in a 3-neck
1000 mL round-bottom flask, and the solution was cooled to
-78.degree. C. Ammonia (.about.35 mL) was condensed into the flask,
then lithium metal was added (wire, 225 mg, 32.4 mmol) in portions
over 10 min. The reaction mixture was stirred at -78.degree. C. for
1 h, quenched with methanol (50 mL) and H.sub.2O (50 mL). The
reaction was allowed to stir overnight at room temperature to allow
NH.sub.3 to evaporate, then it was diluted with ethyl acetate (300
mL), washed with H.sub.2O and brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified on silica gel,
eluting with 15%-25% ethyl acetate-hexanes, to afford the title
compound as a brown oil (999 mg, 55%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 6.82 (t, 1H, J=7.6 Hz), 6.44 (d, 1H, J=7.1 Hz), 6.35 (d,
1H, J=7.5 Hz), 4.80 (s, 2H), 4.78 (t, 1H, J=3.8 Hz), 3.78 (q, 2H,
J=7.1 Hz), 3.36 (q, 2H, 4.8 Hz), 3.00 (t, 2H, J=4.9 Hz), 1.26 (t,
3H, J=7.1 Hz); MS (DCI.sup.+) m/z 190 (M+H).
Example 1F
2-ethoxy-8-isothiocyanato-1,4-dihydronaphthalene
A solution of the product of Example 1E (200 mg, 1.06 mmol) in
dichloromethane (2.5 mL) was added to a solution of
O,O-dipyridin-2-yl thiocarbonate (246 mg, 1.06 mmol) in
dichloromethane (5 mL) at room temperature. After stirring at room
temperature for 18 hours, the mixture was concentrated, then
filtered through silica gel and eluted with 5% ethyl
acetate-hexane. Evaporation of the filtrate in vacuo afforded the
title compound as a pale pink solid, 225 mg (92%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.21-7.27 (m, 3H), 4.86 (t, 1H, J=3.6 Hz),
3.81 (q, 2H, J=7.0 Hz), 3.49 (q, 2H, 4.4 Hz), 3.35 (t, 2H, J=5.2
Hz), 1.27 (t, 3H, J=7.0 Hz); MS (DCI.sup.+) m/z 232 (M+H).
Example 1G
2-azido-1-[4-(trifluoromethyl)phenyl]ethanone
The title compound was prepared using the procedure as described in
Example 1B, substituting
2-bromo-1-[4-(trifluoromethyl)phenyl]ethanone for
2-bromo-1-(4-tert-butylphenyl)ethanone.
Example 1H
N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-[4-(trifluoromethyl)phenyl]-1,3--
oxazol-2-amine
A solution of the product of Example 1F (398 mg, 1.72 mmol), the
product of Example 1G (473 mg, 2.07 mmol), and triphenyl phosphine
(542 mg, 2.07 mmol) in dioxane (9 mL) was heated at 85.degree. C.
for 30 min. The solution was cooled to room temperature and
evaporated in vacuo. The residue was chromatographed on silica gel,
eluting with 25% ethyl acetate-hexane to afford the title compound
as a yellow solid (150 mg, 22%). .sup.1H NMR (DMSO-d.sub.6) .delta.
9.38 (s, 1H), 7.76 (m, 4H), 7.65 (d, 1H, J=8.5 Hz), 7.62 (s, 1H),
7.18 (t, 1H, J=8.2 Hz), 6.97 (d, 1H, J=8.4 Hz), 4.85 (m, 1H), 3.79
(q, 2H, J=6.7 Hz), 3.49 (m, 2H), 3.36 (m, 2H), 1.26 (t, 3H, J=6.8
Hz); MS (ESI.sup.+) m/z 401 (M+H).sup.+.
Example 1I
8-({5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-3,4-dihydronaphth-
alen-2(1H)-one
A solution of the product of Example 1H (150 mg, 0.375 mmol) in
tetrahydrofuran (2.3 mL) was treated with 2N HCl (0.76 mL, 1.52
mmol), and the mixture was heated at 40.degree. C. for 1 hour.
After cooling to room temperature, the solution was brought to pH 8
with saturated NaHCO.sub.3 solution, and extracted with ethyl
acetate. The organic extracts were washed with H.sub.2O, dried over
Na.sub.2SO.sub.4, filtered and evaporated in vacuo to the title
compound as a brown residue (140 mg, 100%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 9.56 (s, 1H), 7.78 (m, 4H), 7.67 (d, 1H,
J=7.8 Hz), 7.62 (s, 1H), 7.22 (t, 1H, J=7.8 Hz), 7.06 (d, 1H, J=7.4
Hz), 3.58 (s, 2H), 3.36 (m, 2H), 3.06 (t, 2H, J=6.8 Hz); MS
(ESI.sup.+) m/z 373 (M+H).sup.+.
Example 2
8-({5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydr-
onaphthalen-2-ol
The product of Example 1I (60 mg, 0.161 mmol) in ethanol (6 mL) was
treated at 0.degree. C. with NaBH.sub.4 (7 mg, 0.184 mmol). The
reaction was stirred at 0.degree. C. for 1 hour and was then poured
into H.sub.2O and extracted with ethyl acetate. The extracts were
dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue
was chromatographed on silica gel eluting with 70%-85% ethyl
acetate-hexane to afford the title compound as a tan solid (34 mg,
56%). .sup.1H NMR (DMSO-d.sub.6) .delta. 9.33 (s, 1H), 7.78 (m,
4H), 7.62 (s, 1H), 7.55 (d, 1H, J=7.4 Hz), 7.11 (m, 1H), 6.88 (d,
1H, J=7.2 Hz), 4.83 (d, 1H, J=4.1 Hz), 3.92 (m, 1H), 2.69-2.98 (m,
4H), 1.86 (m, 1H), 1.62 (m, 1H); MS (ESI.sup.+) m/z 375 (M+H).
Example 3
8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphth-
alen-2-ol
Example 3A
5-(4-tert-butylphenyl)-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol--
2-amine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 1B for the product
of Example 1G.
Example 3B
8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(-
1H)-one
The title compound was prepared using the procedure of Example 1I,
substituting the product of Example 3A for the product of Example
1H.
Example 3C
8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphth-
alen-2-ol
The title compound was prepared using the procedure of Example 2,
substituting the product of Example 3B for the product of Example
1I. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.07 (s, 1H), 7.58 (d, 1H,
J=5.4 Hz), 7.46 (m, 3H), 7.30 (s, 1H), 7.08 (t, 1H, J=7.8 Hz), 6.83
(d, 1H, J=7.1 Hz), 4.80 (d, 1H, J=4.0 Hz), 3.91 (m, 1H), 2.72-2.96
(m, 4H), 1.86 (m, 1H), 1.62 (m, 1H), 1.29 (s, 9H); MS (ESI.sup.+)
m/z 363 (M+H).
Example 4
(2S)-8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydron-
aphthalen-2-ol
The title compound was obtained by chromatographing the product of
Example 3 using chiral HPLC (ChiralPak AD column,
eluent:hexane-ethanol=75/25, flow rate=15 mL/min).
[.alpha.].sub.D.sup.20=-48.0.degree. (c 1.0, MeOH).
Example 5
(2R)-8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydron-
aphthalen-2-ol
The title compound was obtained by chromatographing the product of
Example 3 using chiral HPLC (ChiralPak AD column,
eluent:hexane-ethanol=75/25, flow rate=15 mL/min).
[.alpha.].sub.D.sup.20=+43.2.degree.(c 1.0, MeOH).
Example 6
8-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-
-2-ol
Example 6A
2-azido-1-(4-chlorophenyl)ethanone
The title compound was prepared using the procedure as described in
Example 1B, substituting 2-bromo-1-[4-chlorophenyl]ethan-1-one for
the product of Example 1A.
Example 6B
5-(4-chlorophenyl)-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-am-
ine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 6A for the product
of Example 1G.
Example 6C
8-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)--
one
The title compound was prepared using the procedure as described in
Example 1I, substituting the product of Example 6B for the product
of Example 1H.
Example 6D
8-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-
-2-ol
The title compound was prepared using the procedure as described in
Example 2, substituting the product of Example 6C for the product
of Example 1I. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.16 (s, 1H),
7.43-7.57 (m, 6H), 7.09 (t, 1H, J=7.4 Hz), 6.83 (d, 1H, J=7.0 Hz),
4.80 (d, 1H, J=3.7 Hz), 3.92 (m, 1H), 2.72-2.98 (m, 4H), 1.86 (m,
1H), 1.61 (m, 1H); MS (ESI.sup.+) m/z 341/343 (M+H,
.sup.35Cl/.sup.37Cl).
Example 7
8-{[5-(4-pyrrolidin-1-ylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydron-
aphthalen-2-ol
Example 7A
2-azido-1-(4-pyrrolidin-1-ylphenyl)ethanone
The title compound was prepared using the procedure as described in
Example 1B, substituting
2-bromo-1-(4-pyrrolidin-1-ylphenyl)ethanone for the product of
Example 1A.
Example 7B
N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-(4-pyrrolidin-1-ylphenyl)-1,3-ox-
azol-2-amine
5-(4-chlorophenyl)-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-a-
mine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 7A for the product
of Example 1G.
Example 7C
8-{[5-(4-pyrrolidin-1-ylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthal-
en-2(1H)-one
The title compound was prepared using the procedure as described in
Example 1I, substituting the product of Example 7B for the product
of Example 1H.
Example 7D
8-{[5-(4-pyrrolidin-1-ylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydron-
aphthalen-2-ol
The title compound was prepared using the procedure as described in
Example 2, substituting the product of Example 7C for the product
of Example 1I. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.86 (s, 1H),
7.61 (d, 2H, J=7.2 Hz), 7.37 (d, 1H, J=8.9 Hz), 7.07 (t, 1H, J=7.8
Hz), 7.02 (s, 1H), 6.80 (d, 1H, J=8.2 Hz), 6.57 (d, 2H, J=8.8 Hz),
4.79 (d, 1H, J=4.1 Hz), 3.91 (m, 1H), 3.25 (m, 4H), 2.66-2.97 (m,
4H), 1.99 (m, 4H), 1.89 (m, 1H), 1.62 (m, 1H); MS (ESI.sup.+) m/z
376 (M+H).
Example 8
8-{[5-(4-bromophenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen--
2-ol
Example 8A
2-azido-1-(4-bromophenyl)ethanone
The title compound was prepared using the procedure as described in
Example 1B, substituting 2-bromo-1-(4-bromophenyl)ethanone for the
product of Example 1A.
Example 8B
5-(4-bromophenyl)-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-ami-
ne
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 8A for the product
of Example 1G.
Example 8C
8-{[5-(4-bromophenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-o-
ne
The title compound was prepared using the procedure as described in
Example 1I, substituting the product of Example 8B for the product
of Example 1H.
Example 8D
8-{[5-(4-bromophenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen--
2-ol
The title compound was prepared using the procedure as described in
Example 2, substituting the product of Example 8C for the product
of Example 1I. .sup.1H NMR (DMSO-d.sub.6) .delta.9.17 (s, 1H),
7.43-7.57 (m, 6H), 7.10 (t, 1H, J=7.3 Hz), 6.81 (d, 1H, J=6.8 Hz),
4.80 (d, 1H, J=3.9 Hz), 3.90 (m, 1H), 2.68-2.96 (m, 4H), 1.82 (m,
1H), 1.60 (m, 1H); MS (ESI.sup.+) m/z 385/387 (M+H,
.sup.79Br/.sup.81Br).
Example 9
8-{[5-(4-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-
-2-ol
Example 9A
2-azido-1-(4-methylphenyl)ethanone
The title compound was prepared using the procedure as described in
Example 1B, substituting 2-bromo-1-(4-methylphenyl)ethanone for the
product of Example 1A.
Example 9B
N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-(4-methylphenyl)-1,3-oxazol-2-am-
ine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 9A for the product
of Example 1G.
Example 9C
8-{[5-(4-methylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)--
one
The title compound was prepared using the procedure as described in
Example 1I, substituting the product of Example 9B for the product
of Example 1H.
Example 9D
8-{[5-(4-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydr-
onaphthalen-2-ol
The title compound was prepared using the procedure as described in
Example 2, substituting the product of Example 9C for the product
of Example 1J. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.05 (s, 1H),
7.58 (m, 1H), 7.44 (m, 2H), 7.29 (s, 1H), 7.19 (m, 2H), 7.06 (t,
1H, J=7.5 Hz), 6.83 (d, 1H, J=7.0 Hz), 4.80 (d, 1H, J=4.0 Hz), 3.92
(m, 1H), 2.72-2.96 (m, 4H), 2.31 (s, 3H), 1.84 (m, 1H), 1.63 (m,
1H); MS (ESI.sup.+) m/z 321 (M+H).
Example 10
8-{[5-(4-methoxyphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthale-
n-2-ol
Example 10A
2-azido-1-(4-methoxyphenyl)ethanone
The title compound was prepared using the procedure as described in
Example 1B, substituting 2-bromo-1-(4-methoxyphenyl)ethanone for
the product of Example 1A.
Example 10B
N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-(4-methoxyphenyl)-1,3-oxazol-2-a-
mine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 10A for the product
of Example 1G.
Example 10C
8-{[5-(4-methoxyphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-
-one
The title compound was prepared using the procedure as described in
Example 1I, substituting the product of Example 10B for the product
of Example 1H.
Example 10D
8-{[5-(4-methoxyphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthale-
n-2-ol
The title compound was prepared using the procedure as described in
Example 2, substituting the product of Example 10C for the product
of Example 1I. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.98 (s, 1H),
7.59 (d, 1H, J=7.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.20 (s, 1H), 7.08
(t, 1H, J=7.6 Hz), 7.00 (d, 2H, J=8.8 Hz), 6.82 (d, 1H, J=7.4 Hz),
4.79 (d, 1H, J=4.1 Hz), 3.93 (m, 1H), 3.78 (s, 3H), 2.74-2.98 (m,
4H), 1.85 (m, 1H), 1.63 (m, 1H); MS (ESI.sup.+) m/z 337 (M+H).
Example 11
8-[(5-phenyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol
Example 11A
2-azido-1-phenylethanone
The title compound was prepared using the procedure as described in
Example 1B, substituting 2-bromo-1-phenylethanone for the product
of Example 1A.
Example 11B
N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-phenyl-1,3-oxazol-2-amine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 11A for the product
of Example 1G.
Example 11C
8-[(5-phenyl-1,3-oxazol-2-yl)amino]-3,4-dihydronaphthalen-2(1H)-one
The title compound was prepared using the procedure as described in
Example 1I, substituting the product of Example 11B for the product
of Example 1H.
Example 11D
8-[(5-phenyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol
The title compound was prepared using the procedure as described in
Example 2, substituting the product of Example 11C for the product
of Example 1I. .sup.1H NMR (DMSO-d.sub.6) 9.11 (s, 1H), 7.59 (m,
3H), 7.41 (t, 2H, J=7.7 Hz), 7.37 (s, 1H), 7.25 (t, 1H, J=7.5 Hz),
7.09 (t, 1H, J=7.5 Hz), 6.84 (d, 1H, J=7.1 Hz), 4.80 (d, 1H, J=4.1
Hz), 3.93 (m, 1H), 2.73-2.99 (m, 4H), 1.86 (m, 1H), 1.62 (m, 1H);
MS (ESI.sup.+) m/z 307 (M+H).
Example 12
8-{[5-(1-adamantyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2--
ol
Example 12A
1-(1-adamantyl)-2-azidoethanone
The title compound was prepared using the procedure as described in
Example 1B, substituting 1-(1-adamantyl)-2-bromoethanone for the
product of Example 1A.
Example 12B
5-(1-adamantyl)-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-amine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 12A for the product
of Example 1G.
Example 12C
8-{[5-(1-adamantyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one
The title compound was prepared using the procedure as described in
Example 1I, substituting the product of Example 12B for the product
of Example 1H.
Example 12D
8-{[5-(1-adamantyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2--
ol
The title compound was prepared using the procedure as described in
Example 2, substituting the product of Example 12C for the product
of Example 1I. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.64 (s, 1H),
7.55 (d, 1H, J=7.7 Hz), 7.05 (t, 1H, J=7.6 Hz), 6.77 (d, 1H, J=7.1
Hz), 6.41 (s, 1H), 4.76 (d, 1H, J=4.1 Hz), 3.90 (m, 1H), 2.72-2.94
(m, 3H), 1.63-2.05 (m, 18H); MS (ESI.sup.+) m/z 365
(M+H).sup.+.
Example 13
8-[(5-methyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol
Example 13A
1-azidoacetone
The title compound was prepared using the procedure as described in
Example 1B, substituting 1-chloroacetone for the product of Example
1A.
Example 13B
N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-methyl-1,3-oxazol-2-amine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 13A for the product
of Example 1G.
Example 13C
8-[(5-methyl-1,3-oxazol-2-yl)amino]-3,4-dihydronaphthalen-2(1H)-one
The title compound was prepared using the procedure as described in
Example 1I, substituting the product of Example 13B for the product
of Example 1H.
Example 13D
8-[(5-methyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol
The title compound was prepared using the procedure as described in
Example 2, substituting the product of Example 13C for the product
of Example 1I. .sup.1H NMR (DMSO-d.sub.6) m/z .delta. 8.64 (s, 1H),
7.55 (d, 1H, J=8.1 Hz), 7.03 (t, 1H, J=7.8 Hz), 6.76 (d, 1H, J=7.4
Hz), 6.48 (s, 1H), 4.77 (d, 1H, J=4.1 Hz), 3.90 (m, 1H), 2.63-2.93
(m, 4H), 2.20 (s, 3H), 1.83 (m, 1H), 1.60 (m, 1H); MS (ESI.sup.+)
m/z 245 (M+H).sup.+.
Example 14
8-{[5-(2-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-
-2-ol
Example 14A
2-azido-1-(2-methylphenyl)ethanone
The title compound was prepared using the procedure as described in
Example 1B, substituting 2-bromo-1-(2-methylphenyl)ethanone for the
product of Example 1A.
Example 14B
N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-(2-methylphenyl)-1,3-oxazol-2-am-
ine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 14A for the product
of Example 1G.
Example 14C
8-{[5-(2-methylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)--
one
The title compound was prepared using the procedure as described in
Example 1I, substituting the product of Example 14B for the product
of Example 1H.
Example 14D
8-{[5-(2-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-
-2-ol
The title compound was prepared using the procedure as described in
Example 2, substituting the product of Example 14C for the product
of Example 1I. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.11 (s, 1H),
7.54-7.63 (m, 2H), 7.07-7.30 (m, 5H), 6.84 (d, 1H, J=7.1 Hz), 4.81
(d, 1H, J=4.1 Hz), 3.92 (m, 1H), 2.68-2.99 (m, 4H), 2.40 (s, 3H),
1.84 (m, 1H), 1.62 (m, 1H); MS (ESI.sup.+) m/z 321 (M+H).sup.+.
Example 15
8-{[5-(3-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-
-2-ol
Example 15A
2-azido-1-(3-methylphenyl)ethanone
The title compound was prepared using the procedure as described in
Example 1B, substituting 2-bromo-1-(3-methylphenyl)ethanone for the
product of Example 1A.
Example 15B
N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-(3-methylphenyl)-1,3-oxazol-2-am-
ine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 15A for the product
of Example 1G.
Example 15C
8-{[5-(3-methylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)--
one
The title compound was prepared using the procedure as described in
Example 1I, substituting the product of Example 15B for the product
of Example 1H.
Example 15D
8-{[5-(3-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-
-2-ol
The title compound was prepared using the procedure as described in
Example 2, substituting the product of Example 15C for the product
of Example 1I. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.08 (s, 1H),
7.58 (d, 1H, J=7.3 Hz), 7.26-7.39 (m, 4H), 7.04-7.12 (m, 2H), 6.83
(d, 1H, J=7.2 Hz), 4.81 (d, 1H, J=4.1 Hz), 3.93 (m, 1H), 2.73-2.97
(m, 4H), 2.33 (s, 3H), 1.86 (m, 1H), 1.61 (m, 1H); MS (ESI.sup.+)
m/z 321 (M+H).
Example 16
8-[(5-benzyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol
Example 16A
1-bromo-3-phenylacetone
To a suspension of CuBr (0.143 g, 0.997 mmol) in 25 mL dry ether
was slowly added 1M phenylmagnesium bromide (10 mL, 10 mmol).
Epibromohydrin (0.87 mL, 10.5 mmol) was then added dropwise. The
reaction mixture was allowed to stir at -78.degree. C. to room
temperature overnight, poured into H.sub.2O and extracted with
ether. The extracts were washed with H.sub.2O and brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated in vacuo. The crude
alcohol thus obtained was dissolved in acetone (400 mL) and chilled
in ice, and to this solution was added dropwise 6 mL of Jones
reagent (prepared by dissolution of 2.67 g CrO.sub.3 in 2.5 mL
H.sub.2SO.sub.4, followed by dilution with H.sub.2O to 10 mL). The
reaction mixture was stirred at 0.degree. C. for 15 min and was
then evaporated in vacuo. The residue was taken up in ethyl
acetate, washed repeatedly with water and once with brine, dried
over Na.sub.2SO.sub.4, filtered and evaporated to afford the ketone
product as a brown oil (1.6 g, 75%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 7.17-7.35 (m, 5H), 4.45 (s, 2H), 3.94 (s, 2H); MS
(DCI.sup.+) m/z 230 (M+NH.sub.4.sup.+).
Example 16B
1-azido-3-phenylacetone
The title compound was prepared using the procedure as described in
Example 1B, substituting the product of Example 16A for the product
of Example 1A.
Example 16C
5-benzyl-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-amine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 16B for the product
of Example 1G.
Example 16D
8-[(5-benzyl-1,3-oxazol-2-yl)amino]-3,4-dihydronaphthalen-2(1H)-one
The title compound was prepared using the procedure as described in
Example 1I, substituting the product of Example 16C for the product
of Example 1H.
Example 16E
8-[(5-benzyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol
The title compound was prepared using the procedure as described in
Example 2, substituting the product of Example 16D for the product
of Example 1I. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.72 (s, 1H),
7.56-7.63 (m, 3H), 7.23-7.37 (m, 3H), 7.02 (t, 1H, J=7.5 Hz), 6.77
(d, 1H, J=7.3 Hz), 6.56 (s, 1H), 4.74 (d, 1H, J=3.7 Hz), 3.93 (s,
2H), 3.81 (m, 1H), 2.70-2.90 (m, 4H), 1.81 (m, 1H), 1.58 (m, 1H);
MS (ESI.sup.+) m/z 321 (M+H).sup.+.
Example 17
8-[(5-tert-butyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol
Example 17A
1-azido-3,3-dimethylbutan-2-one
A mixture of 1-bromopinacolone (0.5 mL, 3.7 mmol) and NaN.sub.3
(0.48 g, 7.38 mmol) in 50 mL acetone was stirred overnight at room
temperature. It was then poured into brine and extracted with
dichloromethane. The extracts were washed with brine, were dried
over Na.sub.2SO.sub.4, filtered, and were evaporated to afford the
title compound as a yellow oil (524 mg, 100%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 4.39 (s, 2H), 1.10 (s, 9H); MS (DCI.sup.+)
m/z 142 (M+H).sup.+.
Example 17B
5-tert-butyl-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-amine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 17A for the product
of Example 1G.
Example 17C
8-[(5-tert-butyl-1,3-oxazol-2-yl)amino]-3,4-dihydronaphthalen-2(1H)-one
The title compound was prepared using the procedure as described in
Example 1I, substituting the product of Example 17B for the product
of Example 1H.
Example 17D
8-[(5-tert-butyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol
The title compound was prepared using the procedure as described in
Example 2, substituting the product of Example 17C for the product
of Example 1I. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.66 (s, 1H),
7.53 (d, J=7.8 Hz, 1H), 7.01 (t, J=7.8 Hz, 1H), 6.75 (d, J=7.5 Hz,
1H), 6.44 (s, 1H), 4.76 (d, J=3.7 Hz, 1H), 3.94 (m, 1H), 2.61-2.99
(m, 4H), 1.84 (m, 1H), 1.60 (m, 1H), 1.22 (s, 9H); MS (ESI.sup.+)
m/z 287 (M+H).sup.+.
Example 18
8-(methyl
{5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-te-
trahydronaphthalen-2-ol
Example 18A
8-amino-1,2,3,4-tetrahydronaphthalen-2-ol
To the hydrogenation reaction vessel was charged 5 g of
8-amino-2-naphthanol, 0.2 g of 50% w/w NaOH, 100 ml ethanol, and 2
g of Raney Ni (wet 40 wt % load). The vessel was vacuum purged with
hydrogen several times before heating to 85.degree. C. and
maintaining a hydrogen pressure of 1300 psi. The mixture was
filtered after 6 hrs, and the filtrate concentrated to yield a
brown solid. Isolated yield 4.97 g (97%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 1.44-1.68 (m, 1H), 1.79-1.94 (m, 1H),
2.20 (dd, J=16.48, 7.63 Hz, 1H), 2.56-2.85 (m, 3H), 3.85-3.99 (m,
1H), 4.63 (s, 2H), 4.75 (d, J=4.12 Hz, 1H), 6.30 (d, J=7.48 Hz,
1H), 6.44 (d, J=7.78 Hz, 1H), 6.78 (t, J=7.63 Hz, 1H). .sup.13C NMR
(126 MHz, DMSO-d.sub.6) .delta. ppm 27.35, 31.41, 33.36, 65.81,
111.35, 116.48, 119.13, 125.53, 136.00, 146.12.
Example 18B
7-{[tert-butyl(dimethyl)silyl]oxy}-5,6,7,8-tetrahydronaphthalen-1-amine
A mixture of the product of Example 18A (2.33 g, 14.3 mmol),
tert-butylchlorodimethylsilane (2.6 g, 17.2 mmol), and imidazole
(2.9 g, 42.3 mmol) was stirred in 40 mL of dichloromethane at rt
overnight. The mixture was then washed several times with water and
once with brine. Drying over Na.sub.2SO.sub.4, filtered and
evaporation afforded the product as a dark purple oil, 2.6 g (65%).
.sup.1H NMR (DMSO-d.sub.6) .delta. 6.77 (dd, J=7.8, 7.4 Hz, 1H),
6.42 (d, J=7.8 Hz, 1H), 6.28 (d, J=7.4 Hz, 1H), 4.7 (br s, 2H),
4.11 (m, 1H), 2.75 (m, 3H), 2.24 (m, 1H), 1.82 (m, 1H), 1.63 (m,
1H), 0.88 (s, 9H), 0.09 (s, 6H); MS (ESI.sup.+) m/z 278
(M+H).sup.+.
Example 18C
tert-butyl[(8-isothiocyanato-1,2,3,4-tetrahydronaphthalen-2-yl)oxy]dimethy-
lsilane
A solution of the product of Example 18B,
2-(tert-butyldimethylsilyl)-ol (1.4 g, 5.07 mmol) and di-2-pyridyl
thionocarbonate (1.07 g, 4.61 mmol) in 30 mL dichloromethane was
stirred at room temperature overnight. The mixture was evaporated,
then the residue was taken up in 2 mL dichloromethane and filtered
through silica gel, eluting with 5% ethyl acetate-hexane.
Evaporation of the filtrate afforded the product as a dark red oil
(1.165 g, 72%). .sup.1H NMR (DMSO-d.sub.6) .delta. 7.21 (m, 3H),
4.27 (m, 1H), 2.58-3.09 (m, 4H), 1.90 (m, 1H), 1.77 (m, 1H), 0.90
(s, 9H), 0.14 (s, 6H).
Example 18D
N-(7-{[tert-butyl(dimethyl)silyl]oxy}-5,6,7,8-tetrahydronaphthalen-1-yl)-5-
-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-amine
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 18C for the product
of Example 1F.
Example 18E
N-(7-{[tert-butyl(dimethyl)silyl]oxy}-5,6,7,8-tetrahydronaphthalen-1-yl)-N-
-methyl-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-amine
The product of Example 18D (300 mg, 0.615 mmol) in 5 mL
N,N-dimethylformamide was treated with NaH (60% dispersion, 32 mg,
0.8 mmol) at rt. After stirring for 5 minutes, iodomethane (0.15
mL, 2.4 mmol) was added. The reaction was stirred at rt for 24 h,
then it was poured into ethyl acetate and washed several times with
water and once with brine. The organic layer was dried over
Na.sub.2SO.sub.4 and was concentrated. The concentrate was purified
on silica gel, eluting with 5% ethyl acetate-hexane and afforded
the title compound as a brown oil (56 mg, 18%).
Example 18F
8-(methyl{5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tet-
rahydronaphthalen-2-ol
A solution of the product of Example 18E (56 mg, 0.112 mmol) in 6
mL of tetrahydrofuran was treated with a solution of
tetrabutylammonium fluoride (1M-in-tetrahydrofuran, 1 mL, 1 mmol).
The reaction mixture was stirred at rt for 4 h, then the solvent
was evaporated, and the residue was chromatographed on silica gel,
eluting with 70% ethyl acetate-hexane, to afford the title compound
as a tan foam (27 mg, 62%). .sup.1H NMR (DMSO-d.sub.6) .delta. 7.70
(d, J=8.4 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.57 (s, 1H), 7.11-7.22
(m, 3H), 4.78 (d, J=3.7 Hz, 1H), 3.86 (m, 1H), 3.38 (s, 3H),
2.73-2.98 (m, 3H), 2.37 (m, 1H), 1.89 (m, 1H), 1.63 (m, 1H); MS
(ESI.sup.+) m/z 389 (M+H).sup.+.
Example 19
N-[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]-N-(7-hydroxy-5,6,7,8-tetrahydro-
naphthalen-1-yl)acetamide
The product of Example 3C (76 mg, 0.21 mmol) in 2 mL
tetrahydrofuran was stirred with acetic anhydride (0.026 mL, 0.275
mmol) and triethylamine (0.088 mL, 0.63 mmol) at rt for 3 h. The
reaction mixture was then diluted with ethyl acetate and washed
with water and brine. The organic phase was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
chromatographed on silica gel, eluting with 35% ethyl
acetate-hexane and then 60% ethyl acetate-hexane to afford the
title compound as a tan foam (38 mg, 45%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.03 (s, 1H), 7.48 (m, 4H), 7.10 (m, 2H),
6.82 (m, 1H), 4.72 (d, J=3.8 Hz, 1H), 3.92 (m, 1H), 2.84-3.02 (m,
3H), 2.73 (s, 3H), 2.44 (m, 1H), 1.86 (m, 1H), 1.61 (m, 1H), 1.27
(s, 9H); MS (ESI.sup.+) m/z 405 (M+H).sup.+.
Example 20
N.sup.1-(5-p-methylphenyloxazol-2-yl)-5,6,7,8-tetrahydronaphthalene-1,7-di-
amine
Example 20A
(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamic acid benzyl
ester
Benzylchloroformate (6.96 g, 40.8 mmol) was added dropwise to a
solution of Example 18B (10.3 g, 37.1 mmol,) and
diisopropylethylamine (7.20 g, 55.7 mmol) in 120 mL
CH.sub.2Cl.sub.2 at 0.degree. C. The mixture was stirred for 18
hours gradually warming to ambient temperature after which the
volatiles were evaporated under reduced pressure. The residue was
purified on silica gel eluting with 25% EtOAc/hexanes which yielded
the benzyl carbamate as a light brown oil (15.2 g, 36.9 mmol). This
product was taken up in 100 mL THF followed by addition of 1.79 g
(111 mmol) of triethylamine trihydrofluoride. After 24 hours, the
mixture was concentrated under reduced pressure and the residue
partitioned between EtOAc and 1N aq. HCl. The separated organic
layer was washed with 1N aq. HCl, brine, dried (Na.sub.2SO.sub.4),
and concentrated under reduced pressure. The crude product was
triturated with Et.sub.2O, and the solid was collected by vacuum
filtration and dried under vacuum at 50.degree. C. resulting 8.82 g
(80%) of the title compound as a white solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.82 (s, 1H), 7.45-7.30 (m, 5H), 7.14 (d,
J=7.0 Hz, 1H), 7.05 (t, J=7.0 Hz, 1H), 6.90 (d, J=7.0 Hz, 1H), 5.12
(s, 2H), 4.77 (d, J=3.7 Hz, 1H), 3.87 (m, 1H), 2.86 (m, 2H), 2.72
(m, 1H), 2.43 (m, 1H), 1.84 (m, 1H), 1.58 (m, 1H); MS (ESI.sup.+)
m/z 298 (M+H).sup.+.
Example 20B
(7-Azido-5,6,7,8-tetrahydronaphthalen-1-yl)carbamic Acid Benzyl
Ester
To a suspension of the product of Example 20A (5.05 g, 17.0 mmol)
in 100 mL CH.sub.2Cl.sub.2 containing diisopropylethylamine (3.29
g, 25.5 mmol) at 0.degree. C. was added methanesulfonyl chloride
(2.15 g, 18.9 mmol) dropwise. After stirring 2 hours, the volatiles
were evaporated under reduced pressure. The residue was partitioned
between EtOAc and water, and the separated organic layer was washed
with 1N aq. HCl, saturated NaHCO.sub.3, brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The crude product was dissolved in 60 mL DMF followed by
addition of sodium azide. The mixture was heated to 75.degree. C.
for 1.5 hour then concentrated under reduced pressure. The residue
was taken up in EtOAc and washed with water, brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The crude product was triturated with 1:1
Et.sub.2O:hexane and the solid collected by vacuum filtration and
dried in air. The result was 4.68 g (85%) of the title compound as
a pale orange solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.95 (s,
1H), 7.45-7.30 (m, 5H), 7.19 (d, J=7 Hz, 1H), 7.10 (t, J=7 Hz, 1H),
6.94 (d, J=7 Hz, 1H), 5.13 (s, 2H), 4.00 (m, 1H), 2.96 (m, 1H),
2.83 (m, 2H), 2.62 (m, 1H), 1.99 (m, 1H), 1.74 (m, 1H); MS
(ESI.sup.+) m/z 323 (M+H).sup.+.
Example 20C
(7-Amino-5,6,7,8-tetrahydronaphthalen-1-yl)carbamic Acid Benzyl
Ester
Polymer supported triphenylphosphine (9.5 g, 28 mmol) was added to
the product of Example 20B (4.6 g, 14 mmol) in THF (100 mL)
containing 1.3 g (71 mmol) H.sub.2O. The mixture was stirred for 48
hours at ambient temperature, then diluted with THF and filtered
through a pad of celite. The filter cake was washed with 3 solvents
systems sequentially comprising 100% CH.sub.3OH, 1:1
CH.sub.3OH:CH.sub.2Cl.sub.2, and 100% CH.sub.2Cl.sub.2. The
filtrate was concentrated under reduced pressure to provide 3.5 g
(83%) of the title compound. .sup.1H NMR (DMSO-d.sub.6) .delta.
8.81 (s, 1H), 7.45-7.30 (m, 5H), 7.13 (d, J=8 Hz, 1H), 7.05 (t, J=7
Hz, 1H), 6.90 (d, J=7 Hz, 1H), 5.12 (s, 2H), 3.00-2.65 (m, 4H),
2.23 (m, 1H), 1.84 (m, 1H), 1.59 (br s, 2H), 1.37 (m, 1H); MS
(ESI.sup.+) m/z 297 (M+H).sup.+.
Example 20D
(8-Benzyloxycarbonylamino-1,2,3,4-tetrahydronaphthalen-2-yl)carbamic
Acid Tert-butyl Ester
Di-t-butyldicarbonate (2.59 g, 11.9 mmol) was added to a solution
of the product of Example 20C (3.52 g, 11.9 mmol) and
diisopropylethylamine (2.30 g, 17.8 mmol) in 50 mL CH.sub.2Cl.sub.2
at ambient temperature. The mixture was stirred 18 hours and the
volatiles were evaporated under reduced pressure. The residue was
taken up in EtOAc and washed with 1N aq. HCl, saturated
NaHCO.sub.3, brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated under reduced pressure. Flash chromatography (30%
EtOAc/hexanes) yielded 3.73 g (79%) of the title compound as a
white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.87 (br s, 1H),
7.45-7.30 (m, 5H), 7.10 (m, 2H), 6.93 (m, 2H), 5.12 (s, 2H), 3.80
(m, 1H), 2.90 (m, 1H), 2.81 (m, 2H), 2.38 (m, 1H), 1.87 (m, 1H),
1.55 (m, 1H), 1.40 (s, 9H); MS (ESI.sup.+) m/z 419
(M+Na).sup.+.
Example 20E
(8-Amino-1,2,3,4-tetrahydronaphthalen-2-yl)carbamic Acid Tert-butyl
Ester
To a solution of the product of Example 20D (3.73 g, 9.41 mmol) in
80 mL methanol was added 0.75 g 20% Pd(OH).sub.2/C. The mixture was
shaken under 60 psi H.sub.2 for 4 hours. The catalyst was then
filtered and the filtrate concentrated under reduced pressure. The
crude product was purified by flash chromatography eluting with 2%
to 5% CH.sub.3OH/CH.sub.2Cl.sub.2 which gave 2.33 g (94%) of the
title compound as a white solid. .sup.1H NMR (DMSO-d.sub.6) .delta.
6.91 (br d, 1H), 6.77 (t, J=7.6 Hz, 1H), 6.42 (d, J=7.1 Hz, 1H),
6.29 (d, J=7.1 Hz, 1H), 4.69 (br s, 2H), 3.63 (m, 1H), 2.68 (m,
3H), 2.12 (m, 1H), 1.83 (m, 1H), 1.52 (m, 1H), 1.40 (s, 9H); MS
(ESI.sup.+) m/z 263 (M+H).sup.+.
Example 20F
(8-Isothiocyanato-1,2,3,4-tetrahydronaphthalen-2-yl)carbamic Acid
Tert-butyl Ester
The title compound was prepared using the procedure as described in
Example 1F, substituting the product of Example 20E (1.02 g, 3.89
mmol) for 7-ethoxy-5,8-dihydronaphthalen-1-amine. .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.25-7.10 (m, 3H), 7.00 (m, 1H), 3.70 (m,
1H), 2.98 (m, 1H), 2.81 (m, 2H), 2.57 (m, 1H), 1.90 (m, 1H), 1.58
(m, 1H), 1.41 (s, 9H); MS (ESI.sup.+) m/z 305 (M+H).sup.+.
Example 20G
[8-(5-p-methylphenyloxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]ca-
rbamic acid tert-butyl ester
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 20F (188 mg, 0.618
mmol) for the product of Example 1F and the product of Example 9A
(130 mg, 0.741 mmol) for the product of Example 1G. The crude
product was purified by flash chromatography eluting with 2% to 5%
CH.sub.3OH/CH.sub.2Cl.sub.2 followed by 60% EtOAc/hexanes which
gave 215 mg (83%) of the title compound as a yellow amorphous
solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.06 (br s, 1H), 7.60 (d,
J=7.8 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.29 (s, 1H), 7.23 (d, J=8.1
Hz, 2H), 7.10 (t, J=7.8 Hz, 1H), 6.98 (br d, 1H), 6.84 (d, J=7.5
Hz, 1H), 3.65 (m, 1H), 3.02 (m, 1H), 2.83 (m, 2H), 2.42 (m, 1H),
2.31 (s, 3H), 1.87 (m, 1H), 1.58 (m, 1H), 1.39 (s, 9H); MS
(ESI.sup.+) m/z 420 (M+H).sup.+.
Example 20H
N.sup.1-(5-p-methylphenyloxazol-2-yl)-5,6,7,8-tetrahydronaphthalene-1,7-di-
amine
Hydrogen chloride in dioxane (4N, 7 mL, 28 mmol) was added to a
suspension of 199 mg (0.474 mmol) of the product of Example 20G in
1 mL dioxane. After stirring 45 minutes, the mixture was quenched
with 3N NaOH solution, then diluted with EtOAc and poured into
water. The separated organic phase was washed with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The crude product was triturated with Et.sub.2O and the
solid was collected by vacuum filtration. The result was 92 mg
(61%) of the title compound as a pale pink solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 9.02 (br s, 1H), 7.57 (d, J=7.1 Hz, 1H),
7.45 (d, J=8.1 Hz, 2H), 7.28 (s, 1H), 7.23 (d, J=8.1 Hz, 2H), 7.08
(t, J=7.8 Hz, 1H), 6.83 (d, J=7.1 Hz, 1H), 3.05-2.70 (m, 4H), 2.31
(m, 4H), 1.85 (m, 3H), 1.42 (m, 1H); MS (ESI.sup.+) m/z 320
(M+H).sup.+.
Example 21
N.sup.1-[5-(4-Trifluoromethylphenyl)oxazol-2-yl]-5,6,7,8-tetrahydronaphtha-
lene-1,7-diamine
Example 21A
{8-[5-(4-Trifluoromethylphenyl)oxazol-2-ylamino]-1,2,3,4-tetrahydro-naphth-
alen-2-yl}carbamic acid tert-butyl ester
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 20F (215 mg, 0.706
mmol) for the product of Example 1F, and the product of Example 1G
(194 mg, 0.848 mmol). The crude product was purified by flash
chromatography eluting with 20% EtOAc/hexane which gave 123 mg
(37%) of the title compound as a white solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 9.32 (br s, 1H), 7.75 (m, 4H), 7.60 (s, 1H),
7.55 (d, J=7.8 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.98 (br d, 1H),
6.88 (d, J=7.5 Hz, 1H), 3.64 (m, 1H), 3.02 (m, 1H), 2.84 (m, 2H),
2.42 (m, 1H), 1.87 (m, 1H), 1.60 (m, 1H), 1.39 (s, 9H); MS
(ESI.sup.+) m/z 474 (M+H).sup.+.
Example 21B
N.sup.1-[5-(4-Trifluoromethylphenyl)oxazol-2-yl]-5,6,7,8-tetrahydronaphtha-
lene-1,7-diamine
The title compound was prepared using the procedure as described in
Example 20H substituting the product of Example 21A (120 mg, 0.253
mmol) for the product of Example 20G. The crude product was
purified by trituration with Et.sub.2O/hexanes which resulted in 36
mg (38%) of the title compound as a white solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 9.32 (br s, 1H), 7.75 (m, 4H), 7.60 (s, 1H),
7.55 (d, J=7.8 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.87 (d, J=7.8 Hz,
1H), 3.05-2.70 (m, 4H), 2.30 (m, 1H), 1.82 (m, 3H), 1.43 (m, 1H);
MS (ESI.sup.+) m/z 374 (M+H).sup.+.
Example 22
N.sup.1-[5-(2-Fluoro-4-trifluoromethylphenyl)oxazol-2-yl]-5,6,7,8-tetrahyd-
ro-naphthalene-1,7-diamine
Example 22A
2-Azido-1-(2-fluoro-4-trifluoromethylphenyl)ethanone
The title compound was prepared using the procedure as described in
Example 1B, substituting
2-Bromo-1-(2-fluoro-4-trifluoromethylphenyl)ethanone for
2-bromo-1-(4-tert-butylphenyl)ethanone.
Example 22B
{8-[5-(2-Fluoro-4-trifluoromethylphenyl)oxazol-2-ylamino]-1,2,3,4-tetrahyd-
ro-naphthalen-2-yl}carbamic acid tert-butyl ester
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 20F (415 mg, 1.36
mmol) for the product of Example 1F and the product of Example 22A
(404 mg, 1.63 mmol) for the product of Example 1G. The crude
product was purified by flash chromatography eluting with 20% to
60% EtOAc/hexanes which gave 107 mg (16%) of the title compound as
a yellow solid.
Example 22C
N.sup.1-[5-(2-Fluoro-4-trifluoromethylphenyl)oxazol-2-yl]-5,6,7,8-tetrahyd-
ro-naphthalene-1,7-diamine
Iodotrimethylsilane (52 mg, 0.260 mmol) was added dropwise to a
solution of the product of Example 22B (107 mg, 0.218 mmol) in 1 mL
CH.sub.2Cl.sub.2 at ambient temperature. After 15 minutes the
reaction was diluted with CH.sub.2Cl.sub.2 and quenched with 1N aq
NaOH solution. The mixture was stirred 15 minutes and then poured
into water. The separated organic layer was washed with brine,
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
crude product was triturated with Et.sub.2O/hexanes and the solid
collected by vacuum filtration and dried under high vacuum. The
result was 36 mg (42%) of the title compound as a white solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. 9.42 (br s, 1H), 7.75 (m, 3H),
7.52 (d, J=8.1 Hz, 1H), 7.44 (d, J=3.7 Hz, 1H), 7.11 (t, J=7.5 Hz,
1H), 6.88 (d, J=7.5 Hz, 1H), 3.05-2.70 (m, 4H), 2.30 (m, 1H), 1.86
(m, 1H), 1.70 (br s, 2H), 1.43 (m, 1H); MS (ESI.sup.+) m/z 392
(M+H).sup.+.
Example 23
N-[8-(5-p-methylphenyloxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]-
methanesulfonamide
Example 23A
(7-Methanesulfonylamino-5,6,7,8-tetrahydronaphthalen-1-yl)carbamic
Acid Benzyl ester
Methanesulfonyl chloride (176 mg, 1.54 mmol) was added dropwise to
a solution of the product from Example 20C (381 mg, 1.29 mmol) and
diisopropylethylamine (332 mg, 2.57 mmol) in 15 mL CH.sub.2Cl.sub.2
at ambient temperature. The mixture was stirred 30 minutes, diluted
with methylene chloride and poured into water. The separated
organic phase was washed with 1N aq HCl, brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. Flash chromatography (4% CH.sub.3OH/CH.sub.2Cl.sub.2)
yielded 281 mg (58%) of the title compound as a white amorphous
solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.92 (s, 1H), 7.45-7.30
(m, 5H), 7.22 (d, J=7.1 Hz, 1H), 7.15 (m, 1H), 7.08 (t, J=7.5 Hz,
1H), 6.93 (m, 1H), 5.13 (s, 2H), 3.51 (m, 1H), 3.02 (m, 1H), 2.96
(s, 3H), 2.85 (m, 2H), 2.50 (m, 1H+ DMSO), 2.01 (m, 1H), 1.61 (m,
1H); MS (ESI.sup.+) m/z 375 (M+H).sup.+.
Example 23B
N-(8-Amino-1,2,3,4-tetrahydronaphthalen-2-yl)methanesulfonamide
The title compound was prepared using the procedure as described in
Example 20E substituting the product of Example 23A (280 mg, 0.748
mmol) for the product Example 20D. Flash chromatography (5% to 10%
CH.sub.3OH/CH.sub.2Cl.sub.2) gave 129 mg (72%) of the title
compound as a white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 7.20
(d, J=7.5 Hz, 1H), 6.79 (t, J=7.8 Hz, 1H), 6.43 (m, 1H), 6.30 (m,
1H), 4.74 (s, 2H), 3.55 (m, 1H), 2.99 (s, 3H), 2.75 (m, 3H), 2.22
(m, 1H), 1.95 (m, 1H), 1.58 (m, 1H); MS (DCI.sup.+) m/z 241
(M+H).sup.+.
Example 23C
N-(8-Isothiocyanato-1,2,3,4-tetrahydronaphthalen-2-yl)methanesulfonamide
The title compound was prepared using the procedure as described in
Example 1F, substituting the product of Example 23B (125 mg, 0.529
mmol) for 7-ethoxy-5,8-dihydronaphthalen-1-amine. Flash
chromatography eluting with 3% to 6% CH.sub.3OH/CH.sub.2Cl.sub.2
gave 131 mg (89%) of the title compound as a white solid. .sup.1H
NMR (DMSO-d.sub.6) .delta. 7.24 (m, 2H), 7.19 (d, J=7.8 Hz, 1H),
7.14 (m, 1H), 3.66 (m, 1H), 3.09 (m, 1H), 3.00 (s, 3H), 2.85 (m,
2H), 2.66 (m, 1H), 2.01 (m, 1H), 1.69 (m, 1H); MS (DCI.sup.+) m/z
300 (M+NH.sub.4).sup.+.
Example 23D
N-[8-(5-p-methylphenyloxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]-
methanesulfonamide
The title compound was prepared using the procedure as described in
Example 1H, substituting the product of Example 23C (128 mg, 0.453
mmol) for the product of Example 1F and the product of Example 9A
(95 mg, 0.544 mmol) for the product of Example 1G. The crude
product was purified by flash chromatography eluting with 2% to 5%
CH.sub.3OH/CH.sub.2Cl.sub.2 followed by 100% EtOAc which gave 116
mg (64%) of the title compound as a tan solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. 9.13 (s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.46
(d, J=8.1 Hz, 2H), 7.30 (s, 1H), 7.23 (m, 3H), 7.11 (t, J=7.8 Hz,
1H), 6.85 (d, J=7.5 Hz, 1H), 3.58 (m, 1H), 3.11 (m, 1H), 2.99 (s,
3H), 2.87 (m, 2H), 2.56 (m, 1H), 2.31 (s, 3H), 2.01 (m, 1H), 1.66
(m, 1H); MS (ESI.sup.+) m/z 398 (M+H).sup.+.
Example 24
8-(5-Phenylthiazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol
Example 24A
[7-(tert-Butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl]thiourea
A solution of the product of Example 18C (1.25 g, 3.91 mmol) in THF
(50 mL) was treated with 7N methanolic NH.sub.3 (5.6 mL, 3, 9.1
mmol), and the mixture was stirred at room temperature for 6 hours.
The mixture was partitioned between EtOAc and H.sub.2O, and the
separated organic phase was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure.
Silica gel chromatography (98:2 to 95:5 CH.sub.2Cl.sub.2:CH.sub.3OH
eluant) provided the title compound as a pale yellow solid, 1.27 g
(97%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.12 (s, 1H),
6.6-7.8 (br, 2H), 6.99-7.13 (m, 3H), 4.08 (m, 1H), 2.73-2.92 (m,
4H), 1.84-1.92 (m, 1H), 1.60-1.68 (m, 1H). MS (ESI.sup.+) m/z 337
(M+H).
Example 24B
(1-Bromo-2,2-dimethoxyethyl)benzene
(1-Bromo-2,2-dimethoxyethyl)benzene was synthesized according to
the procedure of Rasmussen and Bowadt (Synthesis 1989, 114). A
solution of phenylacetaldehyde (60 g, 500 mmol) in 250 mL MeOH was
treated with 12.5 g of activated 3 .ANG. molecular sieves and was
then brought to reflux with mechanical stirring. Bromine (25.6 mL,
500 mmol) was added dropwise. The mixture was refluxed for 5 hours,
cooled to ambient temperature, and then treated with potassium
carbonate (35.4 g, 257 mmol). Stirring was continued for 1 hour
after which the solids were filtered off. The filtrate was treated
with brine (250 mL), and extracted with pentane (150 mL).
Evaporation of the solvent afforded the title compound as a brown
oil, 77.71 g (63%), which was used without further
purification.
Example 24C
8-(5-Phenylthiazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol
A mixture of the product of Example 24A (200 mg, 0.594 mmol) and
the product of Example 24B (146 mg, 0.596 mmol) was refluxed for 2
hours in a mixture of EtOH (6 mL) and 1N HCl (1 mL). After cooling
to room temperature, the mixture was quenched with saturated
NaHCO.sub.3 solution and was extracted with EtOAc. The extracts
were dried over Na.sub.2SO.sub.4, filtered evaporated under reduced
pressure, and chromatographed on silica gel (95:5 to 92:8
CH.sub.2Cl.sub.2:CH.sub.3OH eluant). The title compound was
afforded as a pale tan solid, 53 mg (28%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 9.29 (s, 1H), 7.57 (m, 2H), 7.46-7.49 (m,
2H), 7.33-7.38 (m, 2H), 7.22 (m, 1H), 7.10 (m, 1H), 6.88 (d, J=7.4
Hz, 1H), 4.82 (d, J=4.0 Hz, 1H), 3.82 (m, 1H), 2.71-2.98 (m, 4H),
1.83-1.93 (m, 1H), 1.57-1.66 (m, 1H). MS (ESI.sup.+) m/z 323 (M+H).
Anal. calcd. For C.sub.19H.sub.18N.sub.2OS: C, 70.78; H, 5.63; N,
8.69. Found: C, 70.91; H, 5.37; N, 8.33.
Biological Activity
In Vitro Data--Determination of Inhibition Potencies
Dulbecco's modified Eagle medium (D-MEM) (with 4.5 mg/mL glucose)
and fetal bovine serum were obtained from Hyclone Laboratories,
Inc. (Logan, Utah). Dulbecco's phosphate-buffered saline (D-PBS)
(with 1 mg/mL glucose and 3.6 mg/l Na pyruvate) (without phenol
red), L-glutamine, hygromycin B, and Lipofectamine.TM. were
obtained from Life Technologies (Grand Island, N.Y.). G418 sulfate
was obtained from Calbiochem-Novabiochem Corp. (San Diego, Calif.).
Capsaicin (8-methyl-N-vanillyl-6-nonenamide) was obtained from
Sigma-Aldrich, Co. (St. Louis, Mo.). Fluo-4 AM
(N-[4-[6-[(acetyloxy)methoxy]-2,7-difluoro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-
-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phen-
yl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-glycine,
(acetyloxy)methyl ester) was purchased from Molecular Probes
(Eugene, Oreg.).
The cDNAs for the human VR1 receptor were isolated by reverse
transcriptase-polymerase chain reaction (RT-PCR) from human small
intestine poly A+RNA supplied by Clontech (Palo Alto, Calif.) using
primers designed surrounding the initiation and termination codons
identical to the published sequences (Hayes et al. Pain 88:
205-215, 2000). The resulting cDNA PCR products were subcloned into
pCIneo mammalian expression vector (Promega) and fully sequenced
using fluorescent dye-terminator reagents (Prism, Perkin-Elmer
Applied Biosystems Division) and a Perkin-Elmer Applied Biosystems
Model 373 DNA sequencer or Model 310 genetic analyzer. Expression
plasmids encoding the hVR1 cDNA were transfected individually into
1321N1 human astrocytoma cells using Lipofectamine.TM.. Forty-eight
hours after transfection, the neomycin-resistant cells were
selected with growth medium containing 800 .mu.g/mL Geneticin
(Gibco BRL). Surviving individual colonies were isolated and
screened for VR1 receptor activity. Cells expressing recombinant
homomeric VR1 receptors were maintained at 37.degree. C. in D-MEM
containing 4 mM L-glutamine, 300 .mu.g/mL G418 (Cal-biochem) and
10% fetal bovine serum under a humidified 5% CO.sub.2
atmosphere.
The functional activity of compounds at the VR1 receptor was
determined with a Ca.sup.2+ influx assay and measurement of
intracellular Ca.sup.2+ levels ([Ca.sup.2+]i). All compounds were
tested over an 11-point half-log concentration range. Compound
solutions were prepared in D-PBS (4.times. final concentration),
and diluted serially across 96-well v-bottom tissue culture plates
using a Biomek 2000 robotic automation workstation
(Beckman-Coulter, Inc., Fullerton, Calif.). A 0.2 .mu.M solution of
the VR1 agonist capsaicin was also prepared in D-PBS. The
fluorescent Ca.sup.2+ chelating dye fluo-4 was used as an indicator
of the relative levels of [Ca.sup.2+]i in a 96-well format using a
Fluorescence Imaging Plate Reader (FLIPR) (Molecular Devices,
Sunnyvale, Calif.). Cells were grown to confluency in 96-well
black-walled tissue culture plates. Then, prior to the assay, the
cells were loaded with 100 .mu.L per well of fluo-4 AM (2 .mu.M, in
D-PBS) for 1-2 hours at 23.degree. C. Washing of the cells was
performed to remove extracellular fluo-4 AM (2.times.1 mL D-PBS per
well), and afterward, the cells were placed in the reading chamber
of the FLIPR instrument. 50 .mu.L of the compound solutions were
added to the cells at the 10 second time mark of the experimental
run. Then, after a 3 minute time delay, 50 .mu.L of the capsaicin
solution was added at the 190 second time mark (0.05 .mu.M final
concentration) (final volume=200 .mu.L) to challenge the VR1
receptor. Time length of the experimental run was 240 seconds.
Fluorescence readings were made at 1 to 5 second intervals over the
course of the experimental run. The peak increase in relative
fluorescence units (minus baseline) was calculated from the 190
second time mark to the end of the experimental run, and expressed
as a percentage of the 0.05 .mu.M capsaicin (control) response.
Curve-fits of the data were solved using a four-parameter logistic
Hill equation in GraphPad Prism.RTM. (GraphPad Software, Inc., San
Diego, Calif.), and IC.sub.50 values were calculated.
The compounds of the present invention were found to be antagonists
of the vanilloid receptor subtype 1 (VR1) receptor with IC.sub.50s
lower than 12 .mu.M, preferably lower than 5 .mu.M, more preferably
less than 1 .mu.M, and most preferably less than 0.1 .mu.M.
In Vivo Data--Determination of Antinociceptive Effect
Experiments were performed on 400 adult male 129J mice (Jackson
Laboratories, Bar Harbor, Me.), weighing 20-25 g. Mice were kept in
a vivarium, maintained at 22.degree. C., with a 12 hour alternating
light-dark cycle with food and water available ad libitum. All
experiments were performed during the light cycle. Animals were
randomly divided into separate groups of 10 mice each. Each animal
was used in one experiment only and was sacrificed immediately
following the completion of the experiment. All animal handling and
experimental procedures were approved by an IACUC Committee. The
Complete Freund's Adjuvant-induced Thermal Hyperalgesia (CFA) assay
described in Pircio et al. Eur J Pharmacol. Vol. 31(2) pages
207-215 (1975). Chronic inflammatory hyperalgesia was induced in
one group of rats following the injection of complete Freund's
adjuvant (CFA, 50%, 150 .mu.L) into the plantar surface of the
right hindpaw 48 hours prior to testing. Thermal nociceptive
thresholds were measured in three different groups of rats. The
ED.sub.50s, were determined based on the oral administration.
The in vitro and in vivo data demonstrates that compounds of the
present invention antagonize the VR1 receptor and are useful for
treating pain, bladder overactivity, and urinary incontinence.
* * * * *